Cancer and stroke: commonly encountered by clinicians, but little evidence to guide clinical approach

 Obviously the solution is to not have your stroke while you have cancer.

Cancer and stroke: commonly encountered by clinicians, but little evidence to guide clinical approach

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Malin Woock, Nicolas Martinez-Majander, David J. Seiffge, ...

First Published June 28, 2022 Review Article 

https://doi.org/10.1177/17562864221106362

Article information

Abstract

The association between stroke and cancer is well-established. Because of an aging population and longer survival rates, the frequency of synchronous stroke and cancer will become even more common. Different pathophysiologic mechanisms have been proposed how cancer or cancer treatment directly or via coagulation disturbances can mediate stroke. Increased serum levels of D-dimer, fibrin degradation products, and CRP are more often seen in stroke with concomitant cancer, and the clot retrieved during thrombectomy has a more fibrin- and platelet-rich constitution compared with that of atherosclerotic etiology. Multiple infarctions are more common in patients with active cancer compared with those without a cancer diagnosis. New MRI techniques may help in detecting typical patterns seen in the presence of a concomitant cancer. In ischemic stroke patients, a newly published cancer probability score can help clinicians in their decision-making when to suspect an underlying malignancy in a stroke patient and to start cancer-screening studies. Treating stroke patients with synchronous cancer can be a delicate matter. Limited evidence suggests that administration of intravenous thrombolysis appears safe in non-axial intracranial and non-metastatic cancer patients. Endovascular thrombectomy is probably rather safe in these patients, but probably futile in most patients placed on palliative care due to their advanced disease. In this topical review, we discuss the epidemiology, pathophysiology, and prognosis of ischemic and hemorrhagic strokes as well as cerebral venous thrombosis and concomitant cancer. We further summarize the current evidence on acute management and secondary preventive therapy.

Keywords

cancer, cerebral venous thrombosis, clot, diagnostics, hemorrhagic stroke, intracerebral hemorrhage, ischemic stroke, risk, stroke, therapy

Introduction

Cancer and stroke are leading causes of death and disability worldwide. Approximately 40% of all human beings will harbor a malignancy during their lifetimes.¹ Similarly, approximately 25% will experience a stroke.² Both diseases are devastating with high mortality, morbidity, sufferings, and costs. Fortunately, both cancer and stroke treatments took major leaps during the last two decades. While both diseases represent major global health problems, they may occur in the same individual as several lines of evidence suggest an association between several cancer types and various stroke subtypes. About 10% of patients presenting with stroke have a malignancy.³ With aging populations globally, we can expect higher rates already in the forthcoming decades. Patients with malignancies often have similar risk factors as stroke patients, but a clear increase in stroke risks in patients with malignancy occurs without doubt. The mechanisms behind this association are manifold, and not all appropriately explored. From a clinical perspective, an important question is in which stroke patients it is worthwhile and cost-effective to screen for occult cancer. The other relevant clinical question is how to treat patients simultaneously having stroke and cancer, given the increased risk of thrombosis and bleeding at the same time. In the last decades, several encouraging scientific advances in both diagnostics and treatment strategies have greatly changed the course of disease for many patients suffering from cancer or cerebrovascular disease with a prolonged survival rate. This review critically examines the existing data on relationships between cancer and cerebrovascular disease and suggests some approach strategies for clinicians meeting such patients in their practice.

Association between cancer and different subtypes of stroke

The connection between cancer and stroke is well known.^4,5 In older studies,^6,7 ischemic stroke and intracranial hemorrhage were thought to account for equal parts of cerebrovascular disease in cancer patients. A more recent study demonstrated that ischemic stroke is more frequent in cancer patients, however, accounting for approximately 90% of all strokes, similarly to that of the general stroke population.⁴

A nation-wide registry study from the United States confirmed that 1 in 10 hospitalized ischemic stroke patients has co-morbid cancer, and another study showed that about 20% of patients with cryptogenic stroke have occult malignancy at the time of their stroke.^3,8 Studies restricted to those with active cancer (defined as cancer diagnosis, metastasis of known cancer, recurrent cancer, or receiving cancer treatment, all within 6–12 months before or after stroke onset) report frequencies up to 5% among patients with ischemic stroke. This is significantly higher than the general population.^9–11 Over the last decades, stroke admissions among patients with cancer have remained stable despite a significant decrease in the general population, and the proportion of patients with concomitant cancer among stroke patients has increased.³ This is probably reflecting the positive result of longer life expectancy among the general population, allowing people more time to develop cancer as well as better diagnostics and treatment opportunities for cancer patients improving survival in this group.

In accordance with the study from the United States,³ a recently published meta-analysis showed that the pooled cumulative incidence of cancer within 1 year after an ischemic stroke was 13.6 per 1000, being notably higher in studies focusing on cryptogenic stroke and in those reporting cancer screening.¹² One autopsy study conducted in 1985 indicated that 15% of cancer patients had evidence of cerebrovascular disease upon death.⁷ Several large observational studies have confirmed a substantially increased short-term risk of ischemic and hemorrhagic strokes in patients with newly diagnosed solid or hematological cancers.^4,13–15 Solid tumors in advanced stage disease of the lung, pancreatic, and colorectal cancers seem to carry the highest stroke risk.^4,11,16 Other studies reported high incidence of stroke in breast and prostate cancer.^3,9 (Box 1) A vast increase in stroke risk is also seen in metastatic disease, indicating a more advanced disease.¹⁵ Stroke can be the initial presentation of cancer¹⁶ or follow a cancer diagnosis, however,¹³ and the risk of stroke remains elevated even over 10 years following cancer diagnosis.¹⁵

Box 1. The most common types of cancer seen in ischemic stroke, hemorrhagic stroke, and cerebral venous thrombosis.

Box 1. The most common types of cancer seen in ischemic stroke, hemorrhagic stroke, and cerebral venous thrombosis.

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The clinical features associated with active cancer in patients with acute ischemic stroke (AIS) are the presence of venous thromboembolism (VTE), cryptogenic stroke subtype, and lower frequency of traditional cardiovascular risk factors, for example, diabetes mellitus and high low-density lipoprotein (LDL) cholesterol levels.⁹ Studies investigating TOAST (Trial of Org 10172 in Acute Stroke Treatment) subtypes among patients with ischemic stroke and concomitant cancer reported cryogenic stroke to be the most frequent subtype.^14,17,18 Furthermore, Cestari et al.¹⁹ reported embolic ischemic stroke to be more common than non-embolic in ischemic stroke patients with underlying cancer, comprising 54% compared with 46%.

The risk of hemorrhagic stroke in patients with cancer has been investigated in a number of studies. A large nation-wide population-based Swedish study showed that cancer patients had 2.2 times increased risk for a hemorrhagic stroke in the first 6 months following a cancer diagnosis.¹⁵ The risk remained slightly increased (1.2 times) during the following 10 years. Cancers involving the central nervous system, leukemia, endocrine gland, small intestine, and kidney were associated with the highest risk of stroke in this study, and similar results were seen in a more recently published study.⁴

Intracerebral hemorrhage (ICH) is the most frequent type of intracranial hemorrhage associated with cancer.^7,20 Studies of patients with non-traumatic ICH report a wide incidence range for concomitant cancer, from 0.2% to 15%.^21–25 The highest incidence was found in a more recently published study from Japan.²¹ Two of the five studies investigating concomitant cancer among patients presenting with non-traumatic ICH excluded patients with previous primary brain tumors and metastatic brain tumors. The incidences of concomitant cancer in these studies were 3.8% and 15%, respectively.^21,24 Compared with cancer-free patients with ICH, patients with underlying cancer were older, more often male, had received anticoagulation before ICH, had higher prestroke scores according to the Charlson Comorbidity Index, and lower prevalence of diabetes mellitus and arterial hypertension.²⁴ Lower hemoglobin (Hb) levels were typically observed in the cancer group, but platelet count was in the normal range similar to the cancer-free study group.²¹

The data from a large US cancer center suggest that 46% of cancer-associated intracranial hemorrhages are caused by coagulopathy and 61% by intratumoral hemorrhage from an intracranial neoplasm.²⁰ A single-center cohort study of intracranial neoplasm patients reported a frequency of ICH of 2.4%.²⁵ Solid systemic tumors most commonly associated with ICH are lung, melanoma, breast, and renal cancers. This is probably mainly because of their high incidence in the population and frequent metastasis to the brain.^6,20 Prostate cancer accounted for 5% of ICH in one study.²⁰ Among primary brain tumors, glioblastoma multiforme is most often associated with ICH.^6,25 Among the hematological cancers, leukemia is the one most commonly associated with ICH.⁶ Cerebral venous thrombosis (CVT) is a rare cause of stroke with an incidence of 1.32–1.75 per 100,000 individuals.^26–29 Not only are malignancies a risk factor of CVT, but also a predictor of poor outcome.^30,31 The data from cohort studies suggest prevalence of malignancy of 7–10% among patients diagnosed with CVT.^30,32–34 One case–control study reported increased prevalence of malignancy among CVT patients (53/594, 8.9%) as compared with controls (160/6278, 2.5%) despite younger age among cases.³¹ Cancer types with the highest risk of CVT were lung cancer [adjusted odds ratio (aOR) = 32.4], hematological cancer (aOR = 25.1), gastrointestinal cancer (aOR = 5.8), and breast cancer (aOR = 2.6). The association with CVT was particularly high within the first year after diagnosis of cancer. Another study from the same researchers showed that while cancer history was found in 9.3% of CVT patients younger than 55 years of age, it was 24.4% for those 55 years or older.³⁵ Such high probability should alert physicians to remember cancer as a potential underlying factor especially in older CVT patients.

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