Authors

  1. Figuracion, Karl Cristie F.
  2. Jung, Wonkyung
  3. Martha, Sarah R.

Abstract

ABSTRACT: INTRODUCTION: Primary brain tumors are the leading cause of cancer mortality in the United States affecting approximately 90,000 Americans each year. A major complication for brain tumor survivors is acute ischemic stroke (AIS). Currently, there are limited research to provide guidelines for AIS prevention and management in adult brain tumor survivors. The purpose of this review is to discuss the most common risk factors for AIS in adult brain tumor survivors along with best evidence for assessment, screening, and strategies to prevent AIS in this population. METHODS: Relevant literature was identified by searching CINAHL and PubMed databases using the following keywords: "brain tumor survivors," "adults," "stroke," "risk factors," "guidelines," "prevention," and "management". Articles not pertaining to adult brain tumor survivors and AIS were excluded. RESULTS: The location of the tumor, dose, extent, and type of radiation contribute to the development of vascular injury and subsequent carotid stenosis among brain tumor survivors. Endothelial growth factor inhibitor and chemotherapy drugs induces vascular remodeling. Other symptoms such as neurological impairments and co-morbidities are also present among brain tumor survivors. Furthermore, AIS increases from the time of primary brain tumor diagnosis and incidence further increases among patients who were diagnosed with a brain tumor as a child. CONCLUSION: Nurses play a key role in the assessment, prevention, and identifying individuals who are at risk of AIS during brain tumor survivorship. Engaging patients and their caregivers on minimizing their risks of AIS is crucial in the outpatient setting. Annual surveillance visits that include intracranial artery imaging should be used to identify individuals considered most at risk for developing AIS symptoms.

 

Article Content

Primary brain tumors and other central nervous system tumors are the leading cause of cancer mortality in men (<40 years old) and in women (<20 years old) and affect approximately 90 000 Americans each year.1,2 Advances in cancer treatments have led to longer survival in patients with brain tumors. A major complication for brain tumor survivors, defined as those off active treatment, is acute ischemic stroke (AIS).3 AIS becomes more clinically relevant because these patients live longer and the exact prevalence is currently unknown. Currently, there is limited research to provide guidelines for AIS prevention and management in adult brain tumor survivors. For example, the National Comprehensive Cancer Network provides cancer survivorship guidelines for post-cancer therapy with the goal of preventing long-term morbidity and mortality but does not discuss the prevention of AIS.4 In addition, recent guidelines published by the American Heart Association/American Stroke Association (AHA/ASA) detail the prevention and management of AIS yet do not mention the risk of AIS for cancer survivors including patients with brain tumors.3 To better understand the risk of AIS in adult brain tumor survivors, a scientific literature review was conducted to translate evidence to practice. In this review, we will discuss the most common risk factors for AIS in brain tumor survivors along with best evidence for assessment, screening, and treatment to prevent AIS in this population. In addition, we will discuss implications for nursing care in this population.

 

Methods

Relevant literature was identified by searching CINAHL and PubMed databases using the following keywords: "brain tumor survivors," "adults," "stroke," "risk factors," "guidelines," "prevention," and "management." The following restriction criteria were used to narrow the search to the most relevant articles: publication year from 2000 to 2021, English language, adult (>=18 years old), and humans. The literature review was conducted on January 19, 2021; the first and corresponding authors provided the initial screening of literature and full-text reviews. Articles not pertaining to adult brain tumor survivors and AIS were excluded. Relevant articles were identified first by the initial screening of titles and abstracts, followed by full-text review.

 

Acute Ischemic Stroke Prevention

Risk Factors for AIS Related to Demographics and Brain Tumor-Associated Treatments

In this section, we discuss risk factors for AIS among adult brain tumor survivors including demographic factors and brain tumor-associated treatments (eg, radiation, systemic endothelial growth factors inhibitors, chemotherapy, and corticosteroids). In addition, we discuss the complications associated with brain tumors and from brain tumor-associated treatments that negatively impact patient symptoms and outcomes.

 

The incidence of AIS increases with age; older adults (>=65 years old) account for at least 70% of reported cases.5 Additional risk factors for AIS in the general population include sedentary lifestyle, smoking, and preexisting conditions (eg, hypertension, type 2 diabetes, hyperlipidemia, obstructive sleep apnea, depression, obesity, and cancer) as well as a family history of AIS.3 The risk of AIS among all cancer patients is twice as high compared with the general population, with a 7-fold increased risk among brain tumor survivors.6 The potential for AIS increases from the time of primary brain tumor diagnosis (median age at diagnosis is 60 years), and incidence further increases among patients who were given a diagnosis of a brain tumor as a child.7-9

 

Patients with a brain tumor often receive cranial irradiation as part of their treatment. The location of the tumor, dose, extent, and type of radiation contribute to the development of vascular injury and subsequent carotid stenosis among brain tumor survivors.7,8 Radiation-induced intracranial artery stenosis increases the risk of AIS by initiating inflammation that may accelerate the progression of atherosclerosis and lead to hypertension.7 A radiation dose greater than 54 centigray (cGy) to the posterior fossa and the region surrounding the Circle of Willis increases the risk of AIS among brain tumor survivors by 9%, with each additional 100 cGy increasing risk by 5%.10,11 Another study evaluated the AIS rate among patients with meningioma who received stereotactic radiotherapy compared with those receiving proton-photon radiotherapy and found that the rate of AIS was 12 times lower in stereotactic radiotherapy (1.7%) than proton-photon radiotherapy (20.5%) at 5.6 years after radiation.12

 

Systemic treatments of brain tumors that induce vessel injury are endothelial growth factor inhibitors and chemotherapy drugs. Vascular endothelial growth factor (VEGF) inhibitor treatments (eg, bevacizumab) are prescribed to patients with glioma to inhibit tumor angiogenesis and to manage cerebral edema, especially those who cannot tolerate steroids. Bevacizumab is used to limit radiation necrosis by stabilizing the permeability of the blood-brain barrier.13 Unfortunately, VEGF inhibitors may lead to hypertension; VEGF has vascular remodeling effects that block VEGF pathways from producing vasodilatory mediators (eg, nitric oxide). Vascular endothelial growth factor inhibitors increase patients' risk of bleeding and thrombolytic events. Cancer patients receiving bevacizumab were found to have a 3-fold increased risk in developing cerebrovascular events (eg, ischemic and hemorrhagic) compared with controls; this risk was doubled for patients receiving a dose of 5 mg/kg per week.14 Aside from bevacizumab, cisplatin chemotherapy used to treat patients with medulloblastoma as part of the Packer regimen can lead to vascular remodeling and hypertension, thus increasing the risk for AIS.15,16

 

Corticosteroids are routinely prescribed to brain tumor patients to manage cerebral edema. Resulting adverse effects of corticosteroids are hyperglycemia and obesity. Obesity often occurs in patients with diabetes and increases the risk for AIS. Rates of long-term conversion of hyperglycemia to diabetes from corticosteroid use among adult brain tumor survivors are unknown. A retrospective analysis found that 22% of patients with brain tumors experienced glucocorticoid-induced diabetes within 7 days of treatment.17 Another study reported persistent hyperglycemia 3 months post treatment among 10% of patients with low-grade glioma.18 Patients with diabetes frequently experience latent complications (eg, increased mortality rates) in brain tumor survivors. In addition, 1 study found 42.6% of brain tumor survivors are overweight;19 however, the study did not indicate whether it was related to previous corticosteroid use, metabolic syndrome, or decreased physical function.

 

Assessment, Screening, and Strategies to Prevent AIS in Brain Tumor Survivors

Providers who are engaged in the long-term care of brain tumor survivors should include the prevention of AIS as part of posttreatment surveillance visits as well as part of patient education. Brain tumor survivors are normally scheduled for follow-up appointments in neuro-oncology clinics. These routine visits are an opportunity to assess for AIS risk. This screening and assessment should include asking patients questions pertaining to their cognitive and functional recovery. Referral to physical, occupation, and speech rehabilitation should be ordered for patients exhibiting poorer cognitive outcomes and physical immobility or worsening functional deficits.20 Resources, support, and education to patients on the importance of remaining active and prescribing an exercise regimen should also be provided and tailored individually.21

 

Traditional Stroke Risk Factors

Collaboration with primary care providers is essential in brain tumor survivorship to coordinate screening for and treatment of hypertension, diabetes, and hyperlipidemia, and to promote healthy behaviors to mitigate the risk of AIS (see Fig 1). Recommendations for treating hypertension among brain tumor survivors is similar to the general population.3 The use of metformin for hyperglycemia has been associated with better survival of patients with high-grade glioma22 and associated with reducing the risk of AIS.23 However, metformin is contraindicated in persons with severe kidney disease (estimated glomerular filtration rate [eGFR < 30 mL/min]) and requires caution and close monitoring by their primary care provider in adults 65 years or older with decreased renal function (estimated glomerular filtration rate [eGFR, 30-45 mL/min]).24 Hyperglycemia is commonly treated with insulin, a hormone that may promote cancer cell proliferation and metastasis in patients with gliomas. Hyperlipidemia is commonly treated with statin therapy. There are no studies evaluating statin use in adult brain tumor survivors. However, an observational study evaluated statin use and the risk for AIS among head, neck, and thorax cancer patients after radiation and found statin use was associated with a reduction in AIS compared with nonusers of statins.25

  
Figure 1 - Click to enlarge in new windowFIGURE 1. Algorithm for brain tumor survivors with 2 different presentations of who are at risk of acute ischemic stroke (AIS). A, Presentation: acute neurological symptoms in diagnosing AIS and the referral to neurologist and/or neurosurgeon for follow-up. B, Presentation: routine posttreatment visit to mitigate risk of AIS among adult brain tumor survivors.

Imaging and Stroke Detection and Prevention

Providers can also use imaging for screening and prevention of AIS in brain tumor survivors. Imaging can be used to screen for vasculopathy anatomical changes that might predispose a brain tumor survivor to AIS and brain tumor recurrence. If imaging abnormalities (eg, ischemic brain tissue, cerebral artery occlusion, and dissection) are identified, providers should initiate a referral to a neurologist and/or neurosurgeon specializing in AIS for further evaluation and intervention. Most brain tumor survivors undergo magnetic resonance imaging (MRI) surveillance post treatment, which are scheduled every 3 months for 24 months, followed by every 6 months for 36 months, and then at annual visits.4 Magnetic resonance angiography or computed tomographic angiography may be combined with routine MRIs to evaluate intracranial arteries as well as veins to determine the location of ischemic brain tissue, site of occlusion, and dissection. Computed tomographic angiography is sensitive in the detection of arterial anatomy in the Circle of Willis and in large vessel occlusion. It is necessary since radiation treatment to the area of the Circle of Willis increases risk of AIS among brain tumor patients.11,26 Previous studies indicated the median time of AIS onset was at 4.9 years from first radiation treatment.10,11 Therefore, starting computed tomographic angiography screening before 5 years post radiation treatment is recommended (see Fig 1). Computed tomographic angiography also provides images of large vessel occlusion in anterior cerebral arteries, middle cerebral arteries, and posterior cerebral arterial to determine therapeutic decision making.27 Computed tomographic angiography is a preferred method of imaging given its sensitivity in evaluating large arterial vessels, as well as the efficiency of completion and likely coverage by insurance for individuals with brain tumors. Magnetic resonance angiography is more sensitive in detecting small vessel disease but is more expensive and involved procedure for the patient.28 In addition, brain tumor survivors may experience stroke-like migraine attacks after radiation therapy syndrome and posterior reversible encephalopathy syndrome. Both syndromes mimic tumor recurrences and AIS symptoms; therefore, MRI is recommended for accurate diagnosis. Referral to a specialist in AIS is recommended for further evaluation and intervention.

 

Imaging Diagnosis of AIS in Brain Tumor Survivors

Neuroimaging provides valuable diagnostic information during an emergent neurological presentation for brain tumor survivors. The most common form of neuroimaging is noncontrast computed tomography, which is often used to rule out hemorrhage and AIS. However, the most sensitive advance imaging techniques for accurately diagnosing the etiology of AIS symptoms among brain tumor survivors are MRI based. Specific types of MRI include apparent diffusion coefficient (ADC), diffusion-weighted image (DWI) sequences, transverse relaxation time-weighted (T2), and fluid-attenuated inversion recovery, all of which can be analyzed for both tumor recurrence and AIS. Depending on the hospital, MRI sequences may not include DWI or ADC and will need to be specified in the order set. Acute ischemic lesions are characterized as high-density bright lesions on DWIs and low-intensity dark lesions on ADC maps. Diffusion-weighted image is sensitive in detecting hyperacute AIS, and providing qualitative and quantitative information about the status of brain tissue. Although MRI is the criterion standard to identify AIS, access to MRI may be limited at community hospitals or in rural areas, or be contraindicated in some patients. Brain tumor survivors with AIS symptoms may need to be transferred to a primary stroke center for accurate diagnosis of AIS and to receive timely effective treatment. Referral to a neurologist and/or neurosurgeon specializing in AIS is recommended.

 

Acute Ischemic Stroke After Treatment for Brain Tumor Survivors

Management and Treatment of AIS

Research and recommendations of AIS treatment in brain tumor survivors off active treatment are limited. Some of the most frequently asked questions concern the use of antithrombotic and anticoagulation therapies. Limited research has been conducted evaluating intravenous thrombolysis (eg, tissue plasminogen activator) in patients with primary or metastatic brain tumors. Persons with malignant primary brain-tumor-associated AIS are reported to have worse outcomes (eg, higher hospital mortality rate, fewer persons with discharge disposition to home, and an increased risk of intracranial hemorrhage) compared with persons with non-brain tumor associated AIS.29 Intravenous thrombolysis may be considered in AIS patients with benign brain tumors (eg, meningioma) but may not be advisable in primary or metastatic brain neoplasms.30

 

Mechanical thrombectomy is another treatment option for brain tumor patients with AIS. A case report suggests mechanical thrombectomy may be beneficial for patients with good premorbid functional status who develop large vessel occlusive strokes.31 Another study reported intracranial hemorrhage rates after endovascular therapy are comparable between cancer and noncancer patients.32 Unfortunately, there are no clinical trial data available evaluating endovascular therapy in brain tumor survivors with AIS.

 

Antithrombotic agents are recommended as a first-line treatment of cancer-associated AIS, especially low-molecular-weight heparin for preventing recurrent thromboses.33 However, antithrombotic agents are reported to increase the risk of bleeding in cancer patients, which might outweigh any potential reductions in recurrent AIS risk. Antiplatelet therapy may be prescribed to brain tumor patients and is also commonly prescribed for AIS patients. When anticoagulation (low-molecular-weight heparin) was compared with antiplatelet therapy (aspirin) in active cancer-related AIS patients, there was no difference between the groups in rates of recurrent thromboembolism or mortality.34 Subsequently, when patients with active cancer-related AIS were randomized to either enoxaparin or aspirin groups, no differences were found in outcomes evaluated (eg, major bleeding, thromboembolic events, and survival).35 There is no published evidence that evaluates use of antithrombotics in brain tumor patients with AIS.

 

Implications for Nursing

Nurses play a key role in the prevention of AIS, including during brain tumor survivorship. Brain tumor survivors experience neurological impairments that can often be progressive and debilitating, requiring long-term support from family members and caregivers. Patient education is one of the pillars of nursing; hence, it is crucial to engage family members and caregivers about the potential of AIS and other long-term sequelae for these patients. Nurses should explain the symptoms of AIS using the AHA/ASA BE-FAST (ie, balance, eyes, face, arm, speech, and time) mnemonic and emphasize that stroke is a medical emergency as well as the importance of calling 911 immediately if symptoms are observed. Advanced practice nurses should address evidence-based lifestyle prevention strategies (diet and exercise recommendations from AHA/ASA guidelines) in patient, family member, and caregiver interactions. For example, cancer guidelines suggest that adults should engage in moderate physical activity at greater than or equal to 150 minutes per week, vigorous physical activity at 75 minutes per week, or regular activity 30 minutes a day for at least 5 days per week. In addition, collaboration among providers (eg, oncology team, primary care providers, rehabilitation, social worker, and mental health professionals), nurses, and advanced practice nurses (nurse practitioners and clinical nurse specialists) can increase the potential to identify early warning signs of patients at risk for AIS. Annual surveillance visits that include intracranial artery imaging (eg, MRI) should be used to identify individuals considered most at risk for developing AIS symptoms.

 

The exact prevalence of AIS among adult brain tumor survivors remains unknown. Further research is needed to better understand the frequency of AIS in brain tumor survivors. Nurse scientists can bridge this gap of knowledge by studying AIS risk factors and incident AIS in the population. Additional research is needed to identify the effects of medications and therapeutic studies in prevention and management in brain tumor survivors pre and post AIS.

 

Acknowledgment

The authors would like to acknowledge Dr Hilaire J. Thompson for her input and critical feedback on the article.

 

References

 

1. Ostrom QT, Cioffi G, Gittleman H, et al. CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2012-2016. Neuro Oncol. 2019;21(suppl 5):v1-v100. [Context Link]

 

2. Rouse C, Gittleman H, Ostrom QT, Kruchko C, Barnholtz-Sloan JS. Years of potential life lost for brain and CNS tumors relative to other cancers in adults in the United States, 2010. Neuro Oncol. 2016;18(1):70-77. [Context Link]

 

3. Benjamin EJ, Muntner P, Alonso A, et al. Heart disease and stroke statistics-2019 update: a report from the American Heart Association. Circulation. 2019;139(10):e56-e528. [Context Link]

 

4. Denlinger CS, Sanft T, Baker KS, et al. Survivorship, version 2.2018, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2018;16(10):1216-1247. [Context Link]

 

5. Mozaffarian D, Benjamin EJ, Go AS, et al. Heart disease and stroke statistics-2015 update: a report from the American Heart Association. Circulation. 2015;131(4):e29-e322. [Context Link]

 

6. Zaorsky NG, Zhang Y, Tchelebi LT, Mackley HB, Chinchilli VM, Zacharia BE. Stroke among cancer patients. Nat Commun. 2019;10(1):5172. [Context Link]

 

7. Murphy ES, Xie H, Merchant TE, Yu JS, Chao ST, Suh JH. Review of cranial radiotherapy-induced vasculopathy. J Neurooncol. 2015;122(3):421-429. [Context Link]

 

8. Hall MD, Bradley JA, Rotondo RL, et al. Risk of radiation vasculopathy and stroke in pediatric patients treated with proton therapy for brain and skull base tumors. Int J Radiat Oncol Biol Phys. 2018;101(4):854-859. [Context Link]

 

9. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2021. CA Cancer J Clin. 2021;71(1):7-33. [Context Link]

 

10. Mueller S, Sear K, Hills NK, et al. Risk of first and recurrent stroke in childhood cancer survivors treated with cranial and cervical radiation therapy. Int J Radiat Oncol Biol Phys. 2013;86(4):643-648. [Context Link]

 

11. 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. [Context Link]

 

12. McClelland S III, Ciporen JN, Mitin T, Jaboin JJ. Long-term stroke risk of single-fraction photon-based stereotactic radiosurgery for meningioma. Clin Neurol Neurosurg. 2018;173:169-172. [Context Link]

 

13. Zhuang H, Shi S, Yuan Z, Chang JY. Bevacizumab treatment for radiation brain necrosis: mechanism, efficacy and issues. Mol Cancer. 2019;18(1):21. [Context Link]

 

14. 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(7):e102484. [Context Link]

 

15. Herrmann J. Common vascular toxicities of cancer therapies. Cardiol Clin. 2019;37(4):365-384. [Context Link]

 

16. Packer RJ, Gajjar A, Vezina G, et al. Phase III study of craniospinal radiation therapy followed by adjuvant chemotherapy for newly diagnosed average-risk medulloblastoma. J Clin Oncol. 2006;24(25):4202-4208. [Context Link]

 

17. Schultz H, Rasmussen BK, Kristensen PL, Jensen AK, Pedersen-Bjergaard U. Early incidence of glucocorticoid-induced diabetes in patients with brain tumors: a retrospective study of the first 7 days of treatment. Neurooncol Pract. 2018;5(3):170-175. [Context Link]

 

18. Chaichana KL, McGirt MJ, Woodworth GF, et al. Persistent outpatient hyperglycemia is independently associated with survival, recurrence and malignant degeneration following surgery for hemispheric low grade gliomas. Neurol Res. 2010;32(4):442-448. [Context Link]

 

19. Wang KW, Fleming A, Johnston DL, et al. Overweight, obesity and adiposity in survivors of childhood brain tumours: a systematic review and meta-analysis. Clin Obes. 2018;8(1):55-67. [Context Link]

 

20. Tankumpuan T, Utriyaprasit K, Chayaput P, Itthimathin P. Predictors of physical functioning in postoperative brain tumor patients. J Neurosci Nurs. 2015;47(1):E11-E21. [Context Link]

 

21. Baksi A, Arda Surucu H, Nal GI. Postcraniotomy patients' readiness for discharge and predictors of their readiness for discharge. J Neurosci Nurs. 2020;52(6):295-299. [Context Link]

 

22. Seliger C, Luber C, Gerken M, et al. Use of metformin and survival of patients with high-grade glioma. Int J Cancer. 2019;144(2):273-280. [Context Link]

 

23. Cheng YY, Leu HB, Chen TJ, et al. Metformin-inclusive therapy reduces the risk of stroke in patients with diabetes: a 4-year follow-up study. J Stroke Cerebrovasc Dis. 2014;23(2):e99-e105. [Context Link]

 

24. Flory J, Lipska K. Metformin in 2019. JAMA. 2019;321(19):1926-1927. [Context Link]

 

25. Boulet J, Pena J, Hulten EA, et al. Statin use and risk of vascular events among Cancer patients after radiotherapy to the thorax, head, and neck. J Am Heart Assoc. 2019;8(13):e005996. [Context Link]

 

26. Bowers DC, Liu Y, Leisenring W, et al. Late-occurring stroke among long-term survivors of childhood leukemia and brain tumors: a report from the childhood cancer survivor study. J Clin Oncol. 2006;24(33):5277-5282. [Context Link]

 

27. Keigher KM. Large vessel occlusion in the acute stroke patient: identification, treatment, and management. Crit Care Nurs Clin North Am. 2020;32(1):21-36. [Context Link]

 

28. Sidorov EV, Feng W, Selim M. Cost-minimization analysis of computed tomography versus magnetic resonance imaging in the evaluation of patients with transient ischemic attacks at a large academic center. Cerebrovasc Dis Extra. 2014;4(1):69-76. [Context Link]

 

29. Murthy SB, Moradiya Y, Shah S, Shastri A, Bershad EM, Suarez JI. In-hospital outcomes of thrombolysis for acute ischemic stroke in patients with primary brain tumors. J Clin Neurosci. 2015;22(3):474-478. [Context Link]

 

30. Fugate JE, Rabinstein AA. Absolute and relative contraindications to IV rt-PA for acute ischemic stroke. Neurohospitalist. 2015;5(3):110-121. [Context Link]

 

31. Merkler AE, Marcus JR, Gupta A, et al. Endovascular therapy for acute stroke in patients with cancer. Neurohospitalist. 2014;4(3):133-135. [Context Link]

 

32. Murthy SB, Karanth S, Shah S, et al. Thrombolysis for acute ischemic stroke in patients with cancer. Stroke. 2013;44(12):3573-3576. [Context Link]

 

33. Bang OY, Seok JM, Kim SG, et al. Ischemic stroke and cancer: stroke severely impacts cancer patients, while cancer increases the number of strokes. J Clin Neurol. 2011;7(2):53-59. [Context Link]

 

34. Navi BB, Singer S, Merkler AE, et al. Recurrent thromboembolic events after ischemic stroke in patients with cancer. Neurology. 2014;83(1):26-33. [Context Link]

 

35. 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(3):379-381. [Context Link]