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Cancer prevalence higher in stroke patients than in the general population: the Dutch String‐of‐Pearls Institute (PSI) Stroke study

Cancer prevalence higher in stroke patients than in the general population: the Dutch... OR IGIN AL AR TICLE Cancer prevalence higher in stroke patients than in the general population: the Dutch String-of-Pearls Institute (PSI) Stroke study a,b b c d,e b J. Wilbers , L. Sondag , S. Mulder , B. Siegerink and E. J. van Dijk on behalf of the Dutch String-of- Pearls Stroke Study Group * a b Center of Expertise for Cancer Survivorship, Radboud University Medical Center, Nijmegen; Donders Institute for Brain, Cognition and Behaviour, Center for Neuroscience, Department of Neurology, Radboud University Medical Center, Nijmegen; Department of Medical Oncology, Radboud University Medical Center, Nijmegen; Department of Epidemiology, Leiden University Medical Center, Leiden, The Netherlands; and Center for Stroke Research Berlin, Charite Universitatsmediz € in Berlin, Berlin, Germany Keywords: Background and purpose: The aim of this study was to assess the prevalence cancer, epidemiology, of cancer and its characteristics in patients with ischemic stroke and to com- risk factors, stroke pare this with cancer prevalence in the general population. Methods: This was a multicenter cohort study with 2736 patients presenting Received 24 January 2019 with ischemic stroke or transient ischemic attack. The prevalence of cancer Accepted 8 July 2019 was assessed by interview and verified by reviewing all medical records. In stroke patients with a history of cancer, we studied the subtype of cancer and European Journal of its treatment characteristics. We used the national database of The Nether- Neurology 2020, 27: 85–91 lands Cancer Registry to calculate population-based age and sex cancer stan- dardized prevalence ratios (SPRs) for patients with ischemic stroke. doi:10.1111/ene.14037 Results: Cancer prevalence in ischemic stroke patients was 12%, correspond- [Correction added on 27 ing to an SPR of 1.2 [95% confidence interval (CI), 1.0–1.3]. Increased SPRs August 2019 after first were observed for cancer of the central nervous system (SPR, 18.2; 95% CI, publication: the title has been 9.0–27.4), head and neck (SPR, 3.4; 95% CI, 2.3–4.6), lower respiratory tract updated in this version.] (SPR, 2.4; 95% CI, 1.5–3.3) and urinary tract (SPR, 2.1; 95% CI, 1.4–2.9), but not for other cancer types. Cardiovascular risk factors, stroke etiology, treatment and outcome were not different between patients with or without a history of cancer. Conclusions: In stroke patients, the prevalence of cancer, most prominently cancer of the central nervous system, head and neck, lower respiratory and urinary tract, was higher than in the general population. Medical treatment for the prevention of stroke in cancer survivors deserves further study. by the sharing of highly prevalent population risk fac- Introduction tors, particularly smoking. Cancer may also have a Cancer and cardiovascular diseases are the two lead- causal relationship with cerebrovascular disease by ing causes of morbidity and mortality worldwide [1]. inducing a hypercoagulable state, non-bacterial An autopsy study in patients with cancer showed that thrombotic endocarditis and tumor compression of 15% had evidence of prevalent cerebrovascular dis- blood vessels. Direct and late toxicity of anticancer ease [2]. This co-occurrence of cancer and cerebrovas- treatment, either radiotherapy (RT)-related vasculopa- cular disease may be explained by the high prevalence thy or chemotherapy-related hypercoagulability, could of both diseases in the general elderly population and also be causative factors [2,3]. A large study of patients with cancer and matched controls showed a Correspondence: J. Wilbers, Center of Expertise for Cancer 3-month increased incidence of stroke in patients with Survivorship, Radboud University Medical Center, PO Box 9101 lung, pancreatic and colorectal cancers [4]. Within a 6500 HB Nijmegen, The Netherlands (tel.: +31 (0) 24 361 3953; sample of 96 ischemic stroke patients with a known fax: +00 312 436 35163; e-mail: Joyce.Wilbers@radboudumc.nl. history of a cancer, the most frequent types of *Members of the Study Group are listed in Appendix S1S1. © 2019 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology 85 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. EUROPEAN JOURNAL O F N EUROLOGY 86 J. WILBERS ET AL. previous cancer were lung (30%), brain (9%) and had died, we also collected oncological information by prostate (9%) [5]. The population of long-term cancer reviewing medical records and contacting the general survivors is growing, and several studies have reported practitioner or treating physician. The interval between on the long-term vascular complications in these cancer and stroke was calculated in years. patients [6–8]. Nevertheless, studies on the prevalence For comparison of our data, we used information and characteristics of cancer in a large cohort of from the database of The Netherlands Cancer Registry, patients presenting with ischemic stroke are lacking. which registers the most important statistics on cancer The purpose of the current study was to investigate in The Netherlands and is managed by the Netherlands the long-term prevalence of previous cancer in Comprehensive Cancer Organisation (Integraal Kanker patients diagnosed with stroke in comparison with Centrum Nederland (IKNL)). Data collected included that in the general population in The Netherlands. incidence, prevalence, survival, mortality and risk of different cancer types, as well as localization and mor- phological classification of tumors. Combining localiza- Materials and methods tion and morphology enables precise classification of From May 2007 until March 2014, we recruited par- diagnosis. The definitions used for cancer in stroke were ticipants in a prospective multicenter cohort study, in accordance with the classification of tumors used by called the String of Pearls Institute, a collaboration of The Netherlands Cancer Registry based on the 10th the eight university medical centers in The Nether- edition of the International Classification for Diseases lands. Details of this study protocol have been (ICD-10). The ICD-10 codes used were: C81–C96, C38, described previously [9]. In short, a national stroke C40–C41, C46–C49, C50, C70–C72, C73–C75, C00– database with a standardized central infrastructure C14, C30–C32, C69, C43–C44, C60–C63, C33–C34, allowed uniform data collection and storage of bioma- C45, C15–C26, C51–C58, C37, C39, C76 and C80. terials in patients presenting with a recent cerebrovas- Basal cell carcinoma and adenoma of the pituitary cular disease. For the current study, we included are not registered by The Netherlands Cancer Registry. patients with ischemic stroke or transient ischemic attack as index event. All local Medical Ethical Com- Data analysis mittees of participating hospitals approved the study. The research was performed according to the princi- Stroke characteristics (cardiovascular risk factors, ples of the Declaration of Helsinki and in accordance stroke etiology, treatment and outcome) in the patients with the Medical Research Involving Human Subjects with and without a history of cancer were compared Act and codes on ‘good use’ of clinical data and bio- after stratification for age. All cancer characteristics logical samples as developed by the Dutch Federation were separately analyzed for patients who had active of Medical Scientific Societies (http://www.wma.net/ cancer (defined as not disease free), had been cancer en/10home/index.html). All patients provided written free ≤5 years [short-term cancer-free patients (CFPs)] informed consent. and had been cancer free >5 years (long-term CFPs). We collected data on age, sex, cardiovascular risk We used Fisher’s test and chi-squared test to assess factors (smoking, hypertension, hypercholesterolemia, unadjusted differences in proportions and a t-test to diabetes mellitus), presence or a history of atrial fibril- assess differences in mean values. In order to deter- lation, previous cardiovascular events (ischemic mine if any cancer type was more common amongst stroke, transient ischemic attack, acute myocardial stroke patients, we compared the 20-year prevalence infarction and peripheral arterial disease), stroke of cancer diagnosis with the 20-year prevalence of severity by means of the National Institutes of Health diagnosis in the Dutch population for specific cancer Stroke Scale score at admission and functional out- localizations. We used data from The Netherlands come at 3 months by the modified Rankin scale score Cancer Registry to calculate the expected number of [10]. Etiology of stroke was classified according to the cases in our cohort, based on its age and sex distribu- modified Trial of Org 10172 in Acute Stroke Treat- tion. We calculated standardized prevalence ratios ment (TOAST) criteria [11]. (SPRs) by dividing the observed cancer number by In the subset of patients with a history of cancer the expected cancer number. (n = 321), we retrospectively collected information by reviewing the clinical records and contacting the general Results practitioner or treating oncological physician about the type and stage of the cancer and treatment (type of We included 2736 patients with a mean (SD) age of chemotherapy, use of angiogenesis inhibitor, RT 65 (14) years of whom 59% were men. Of these dosage and location). In those cases where the patient patients, 321 (12%) had a history of cancer. The total © 2019 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology CANCER PREVALENCE IN STROKE PATIENTS 87 Table 1 Demographics and characteristics of patients with number of cancers was 360. Patients with a history of (n = 321) and without (n = 2415) a history of cancer at the time of cancer were significantly older (mean age diagnosis of ischemic stroke 72  12 years) than patients without a history of can- cer (mean age 64  14 years) (Table 1). There were Stroke Stroke patients patients with without cancer no significant differences in stroke characteristics cancer history history between the patients with and without a history of (n = 321) (n = 2415) P cancer. The majority of strokes were caused by large (12%) (88%) value artery disease in both groups (39%). Demographics Men 186 (58) 1435 (59) 0.77 Age (years) 72  12 64  14 <0.001 Cancer characteristics Risk factors Among the 321 stroke patients with a history of can- Smoking Never 113 (38) 847 (37) 0.18 cer, 13 different types of cancer were identified. The Stopped > 6 months 123 (41) 761 (33) most common primary malignancy locations were Stopped < 6 months 8 (3) 48 (2) male genital tract (16%), breast (16%), digestive tract Current 57 (19) 637 (28) (13%), urinary tract (10%) and head and neck (9%) Hypertension 190 (59) 1271 (53) 0.85 (Table 2). A total of 53% of the patients with cancer Hypercholesterolemia 116 (37) 831 (35) 0.49 were long-term CFPs at the time of stroke. Of the Diabetes 60 (19) 376 (16) 0.86 Atrial fibrillation 53 (17) 286 (12) 0.72 short-term CFPs, 42 (26%) were treated with Alcohol use 158 (56) 1317 (61) 0.31 chemotherapy versus 15% of the long-term CFPs Past arterial events (P < 0.02). Most frequently used chemotherapy IS/TIA 98 (32) 655 (29) 0.97 included platinum-based (45%) or alkylating (33%) AMI 43 (14) 259 (11) 0.82 agents in the short-term CFPs and alkylating (65%) PAD 28 (9) 180 (8) 0.92 Stroke characteristics or antibiotic (55%) agents in the long-term CFPs. A Duration < 24 h 58 (19) 419 (18) 0.57 total of 66 (41%) of the short-term CFPs versus 82 TOAST (47%) of the long-term CFPs had received RT, most LAD 84 (39) 645 (39) 0.05 frequently for head and neck cancer (Table 3). CE 42 (19) 222 (14) In the current cohort of stroke patients, increased SVD 30 (14) 291 (18) Other 62 (28) 480 (29) SPRs were observed for cancer of the central nervous NIHSS score 4 54  5 0.94 system (CNS) [SPR, 18.2; 95% confidence interval Treatment (CI), 9.0–27.4], head and neck (SPR, 3.4; 95% CI, IV thrombolysis 44 (16) 386 (19) 0.29 2.3–4.6), lower respiratory tract (SPR, 2.4; 95% CI, Outcome at 3 months (MRS score) 0 64 (28) 589 (31) 0.20 1.5–3.3) and urinary tract (SPR, 2.1; 95% CI, 1.4–2.9) 1 64 (28) 500 (28) (Table 4). Patients with CNS cancer showed a mean 2 39 (17) 400 (22) cancer–stroke interval of 9.2 years and 40% had an 3 27 (12) 183 (10) undetermined etiology of stroke. A total of 57% of 4 19 (8) 81 (5) patients with CNS cancer had received RT with a 5 2 (1) 24 (1) 6 13 (6) 56 (3) mean (SD) dose of 55 (8) Gy. The subgroup of 23 patients with CNS cancer consisted mostly of glial Data are given as n (%, complete case analysis) and mean  SD. tumors (n = 8) and meningioma (n = 8) AMI, acute myocardial infarct; CE, cardioembolism; IS, ischemic (Appendix S2). Patients with head and neck cancer stroke; IV, intravenous; LAD, large artery disease; MRS, modified had a mean cancer–stroke interval of 7.2 years, Rankin scale; NIHSS, National Institutes of Health Stroke Scale; PAD, peripheral arterial disease; SVD, small vessel disease; TIA, TOAST classification showed mostly large artery dis- transient ischemic attack; TOAST, Trial of Org 10172 in Acute ease (71%) and 44% were current smokers. Patients Stroke Treatment. P value for difference adjusted for age. with lower respiratory tract cancer had a mean cancer–stroke interval of 6 years and 77% were cur- stroke and cancer characteristics, and compares rent or former smokers. Patients with urinary tract these with those in the general population. As can- cancer had a mean cancer–stroke interval of 7.4 years cer survival improves, it is increasingly relevant to and 62% were current or former smokers. have knowledge of and to pay attention to vascular complications in patients with cancer. It is impor- Discussion tant to define types of cancer associated with stroke risk and their specific risk factors. These findings The current study is the first and largest multicenter are useful in the development of prevention study among stroke patients that combines patient, © 2019 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology 88 J. WILBERS ET AL. Table 2 Absolute and relative frequencies of prevalent cancer subtypes at the time of ischemic stroke diagnosis Type of cancer Total (n = 360) Cancer free ≤ 5 years (n = 171) Cancer free > 5 years (n = 189) Male genital tract 59 (16) 36 (21) 23 (12) Breast 57 (16) 16 (9) 41 (22) Digestive tract 48 (13) 23 (14) 25 (13) Urinary tract 35 (10) 19 (11) 16 (9) Head and neck 33 (9) 14 (8) 19 (10) Blood, lymph and bone marrow 28 (8) 14 (8) 14 (7) Lower respiratory tract 27 (8) 15 (9) 12 (6) Skin 26 (7) 10 (6) 16 (9) Central nervous system 20 (6) 16 (9) 4 (2) Female genital tract 15 (4) 4 (2) 11 (6) Endocrine 7 (2) 3 (2) 4 (2) Bone and soft tissue 4 (1) 1 (1) 3 (2) Eye and orbit 1 (0) 0 (0) 1 (1) Data are expressed as absolute n (%). guidelines for patients who survive cancer. The We did not find an increased prevalence of stomach prevalence of cancer was higher in ischemic stroke cancer; however, cancer type distributions differ patients than in the general population. In particu- around the world. The purpose of the current study lar, CNS, head and neck, lower respiratory tract was to investigate the long-term prevalence of previ- and urinary tract cancers were more prevalent in ous cancer in stroke patients in comparison with the ischemic stroke patients than in the age- and sex- general population. We found increased prevalence matched general population. Stroke etiology and ratios of cancer types more associated with long-term outcome did not differ between ischemic stroke survival. Underlying mechanisms for increased risk of patients with and without a cancer history. stroke in these long-term survivors are long-term RT- The strongly increased SPR of CNS cancer in induced vasculopathy or shared risk factors like smok- stroke patients has never been described before. The ing. In contrast, other studies evaluated the more underlying pathology might partly be explained by a short-term risk of stroke in patients with active cancer long-term RT-induced intracranial vasculopathy. [4,18–21]. Increased risk of stroke was reported mostly There are no previous reports of increased stroke risk in lung, pancreatic and colorectal cancers. In these in patients with meningioma. The association of patients, cancer may also have a causal relationship glioblastoma multiforme and ischemic strokes might with stroke by inducing a hypercoagulable state, non- be explained by post-operative complications, late bacterial thrombotic endocarditis and compression of complications of RT, a hypercoagulable state induced blood vessels by the tumor. The discrepancy in cancer by the tumor or vessel occlusion that is caused by an types associated with stroke in long-term survivors adjacent tumor [12,13]. In head and neck cancer, versus patients with active cancer can be explained by post-radiation vasculopathy of the carotid artery is different underlying associated mechanisms. The study the most likely and best-known link with an increased of Selvik et al. of cancer prevalence in stroke patients risk of stroke [7,14]. The relatively high percentage of in Norway [22] was similar to our study setting. In a RT in this type of cancer and the relatively long mean cohort of 1456 ischemic stroke patients, 15.7% of the latency period (9 years) between cancer and stroke patients had one or more cancer diagnosis before support this association. Furthermore, head and neck, stroke. This prevalence of cancer in stroke patients lower respiratory and urinary tract cancer, and stroke was higher than the prevalence of cancer in the gen- have similar risk factors, in particular smoking. Most eral population. These results are similar to the results patients treated with chemotherapy had received plat- of the current study. The added value of the current inum-based or alkylating therapy, which are associ- study is the larger stroke cohort and, more impor- ated with a known increased risk of stroke [15]. The tantly, the reporting of SPRs of different cancer types most frequent cancer types in previous smaller retro- compared with the general population instead of the spective studies in stroke patients included urogenital, reporting of only prevalence of cancer types, which breast, gastrointestinal, hematological and lung [16]. makes comparison of the prevalence of different can- A high frequency of stomach cancer was observed in cer types with the general population more difficult. a retrospective case-control study in stroke patients in Furthermore, we found that stroke characteristics Korea [17]. were not different between patients with or without a © 2019 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology CANCER PREVALENCE IN STROKE PATIENTS 89 Table 3 Characteristics of cancer treatment in an ischemic stroke population Treatment characteristic Total (n = 360) Cancer free ≤ 5 years (n = 171) Cancer free >5 years (n = 189) P value Chemotherapy 68 (20) 42 (26) 26 (15) 0.02 Alkylating 26 (44) 13 (33) 13 (65) 0.04 Platinum-based 21 (36) 17 (45) 4 (20) 0.12 Antibiotic 17 (29) 6 (15) 11 (55) 0.004 Topoisomerase inhibitor 12 (21) 9 (24) 3 (16) 0.73 Antimetabolite 9 (16) 7 (18) 2 (11) 0.70 Antimitotic 9 (16) 3 (8) 6 (30) 0.07 Methotrexate 6 (11) 3 (8) 3 (16) 0.65 Local 7 (13) 4 (11) 3 (16) 0.68 Other 20 (34) 14 (36) 6 (30) 0.87 Other systemic treatments Rituximab 7 (12) 6 (16) 1 (5) 0.48 Tyrosine kinase inhibitor 3 (5) 3 (8) 0 (0) 0.53 Angiogenesis inhibitor 7 (2) 5 (3) 2 (1) 0.39 RT 148 (44) 66 (41) 82 (47) 0.29 Location of RT Head or neck 54 (37) 25 (39) 29 (35) 0.06 Chest 41 (28) 12 (19) 29 (35) Other 52 (35) 28 (43) 24 (29) Dose (Gy) Head or neck 52  15 53  16 50  15 0.51 Chest 51  11 52  14 50  9 0.69 Other 50  30 40  24 62  33 0.08 Data are expressed as n (%) (complete case analysis) and mean  SD. Valid percentages do not add up to 100% due to overlap and multiple treatments. P value for difference between cancer free ≤ 5 years and cancer free > 5 years by chi-squared test and for differences in radiother- apy (RT) dose by independent sample t-test. Table 4 Standardized 20-year prevalence ratio of cancer subtypes in ischemic stroke patients Type of cancer Observed number Expected number SPR 95% CI Male genital tract 56 54 1.0 0.8–1.3 Breast 43 42 1.0 0.7–1.3 Digestive tract 38 46 0.8 0.6–1.1 Urinary tract 31 15 2.1 1.4–2.9 Head and neck 29 9 3.4 2.3–4.6 Blood, lymph and bone marrow 23 18 1.3 0.8–1.8 Lower respiratory tract 26 11 2.4 1.5–3.3 Skin 21 38 0.6 0.3–0.8 Central nervous system 15 1 18.2 9.0–27.4 Female genital tract 5 12 0.4 NA Bone and soft tissue 2 2 1.1 NA Endocrine 4 1 2.7 NA Any cancer 273 238 1.2 1.0–1.3 Expected number calculated from the age-specific 20-year prevalence in the Dutch population (source: Dutch Cancer Registration, www.cijfe rsoverkanker.nl). Cancer diagnosis > 20 years before 2011 was excluded in these analyses. CI, confidence interval; NA, not applicable; SPR, standardized prevalence ratio. SPR for male genital tract, female genital tract and breast cancer was calculated for men only and women only, respectively. 95% CI for cancer types with low prevalence (i.e. <5 cases) could not be calculated. cancer history, which is in line with previous smaller distributions are different over the world and depend retrospective analyses [16,17,23]. on age and sex, it was important that we were able to Our study is the first and largest multicenter study compare the prevalence of the different cancer types in stroke patients in The Netherlands that combined in our stroke cohort with that from the same source patient, stroke and cancer characteristics. Further- population, stratified by age and sex. more, this study compared these characteristics with Our study has some limitations. Patients with a his- those in the general population. As cancer type tory of cancer potentially have a higher likelihood of © 2019 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology 90 J. WILBERS ET AL. being diagnosed with stroke due to long-term surveil- Disclosure of conflicts of interest lance with lower threshold to perform more extensive The authors declare no financial or other conflicts of evaluations. However, we did not observe differences interest. The work described in this study was carried in stroke subtypes or severity between patients with out in the context of the Parelsnoer Institute. PSI is and without a cancer history. If this bias had part of and funded by the Dutch Federation of occurred one would expect more relatively mild University Medical Centers and has received initial strokes in those with a cancer history. Furthermore, funding from the Dutch Government (from 2007 to patients with a history of cancer could have been 2011). more often referred to university medical centers because of their cancer history. This is not very likely because in The Netherlands almost all hospitals pro- Supporting Information vide acute stroke care and patients are referred to the Additional Supporting Information may be found in nearest hospital. Furthermore, we did not observe dif- the online version of this article: ferences between participating hospitals with large specialized oncology departments and those without. Appendix S1. Study group. The retrospective identification and verification of Appendix S2. Characteristics of patients with central cancer cases may have resulted in some misclassifica- nervous system cancer. tion. However, it is unlikely that cancer is under-re- ported by the patients themselves because of the References impact of this disease. Furthermore, the systematic 1. 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Cancer prevalence higher in stroke patients than in the general population: the Dutch String‐of‐Pearls Institute (PSI) Stroke study

Wilbers, J.; Sondag, L.; Mulder, S.; Siegerink, B.; van Dijk, E. J.; ,
European Journal of Neurology , Volume 27 (1) – Jul 29, 2019
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© 2019 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology
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Abstract

OR IGIN AL AR TICLE Cancer prevalence higher in stroke patients than in the general population: the Dutch String-of-Pearls Institute (PSI) Stroke study a,b b c d,e b J. Wilbers , L. Sondag , S. Mulder , B. Siegerink and E. J. van Dijk on behalf of the Dutch String-of- Pearls Stroke Study Group * a b Center of Expertise for Cancer Survivorship, Radboud University Medical Center, Nijmegen; Donders Institute for Brain, Cognition and Behaviour, Center for Neuroscience, Department of Neurology, Radboud University Medical Center, Nijmegen; Department of Medical Oncology, Radboud University Medical Center, Nijmegen; Department of Epidemiology, Leiden University Medical Center, Leiden, The Netherlands; and Center for Stroke Research Berlin, Charite Universitatsmediz € in Berlin, Berlin, Germany Keywords: Background and purpose: The aim of this study was to assess the prevalence cancer, epidemiology, of cancer and its characteristics in patients with ischemic stroke and to com- risk factors, stroke pare this with cancer prevalence in the general population. Methods: This was a multicenter cohort study with 2736 patients presenting Received 24 January 2019 with ischemic stroke or transient ischemic attack. The prevalence of cancer Accepted 8 July 2019 was assessed by interview and verified by reviewing all medical records. In stroke patients with a history of cancer, we studied the subtype of cancer and European Journal of its treatment characteristics. We used the national database of The Nether- Neurology 2020, 27: 85–91 lands Cancer Registry to calculate population-based age and sex cancer stan- dardized prevalence ratios (SPRs) for patients with ischemic stroke. doi:10.1111/ene.14037 Results: Cancer prevalence in ischemic stroke patients was 12%, correspond- [Correction added on 27 ing to an SPR of 1.2 [95% confidence interval (CI), 1.0–1.3]. Increased SPRs August 2019 after first were observed for cancer of the central nervous system (SPR, 18.2; 95% CI, publication: the title has been 9.0–27.4), head and neck (SPR, 3.4; 95% CI, 2.3–4.6), lower respiratory tract updated in this version.] (SPR, 2.4; 95% CI, 1.5–3.3) and urinary tract (SPR, 2.1; 95% CI, 1.4–2.9), but not for other cancer types. Cardiovascular risk factors, stroke etiology, treatment and outcome were not different between patients with or without a history of cancer. Conclusions: In stroke patients, the prevalence of cancer, most prominently cancer of the central nervous system, head and neck, lower respiratory and urinary tract, was higher than in the general population. Medical treatment for the prevention of stroke in cancer survivors deserves further study. by the sharing of highly prevalent population risk fac- Introduction tors, particularly smoking. Cancer may also have a Cancer and cardiovascular diseases are the two lead- causal relationship with cerebrovascular disease by ing causes of morbidity and mortality worldwide [1]. inducing a hypercoagulable state, non-bacterial An autopsy study in patients with cancer showed that thrombotic endocarditis and tumor compression of 15% had evidence of prevalent cerebrovascular dis- blood vessels. Direct and late toxicity of anticancer ease [2]. This co-occurrence of cancer and cerebrovas- treatment, either radiotherapy (RT)-related vasculopa- cular disease may be explained by the high prevalence thy or chemotherapy-related hypercoagulability, could of both diseases in the general elderly population and also be causative factors [2,3]. A large study of patients with cancer and matched controls showed a Correspondence: J. Wilbers, Center of Expertise for Cancer 3-month increased incidence of stroke in patients with Survivorship, Radboud University Medical Center, PO Box 9101 lung, pancreatic and colorectal cancers [4]. Within a 6500 HB Nijmegen, The Netherlands (tel.: +31 (0) 24 361 3953; sample of 96 ischemic stroke patients with a known fax: +00 312 436 35163; e-mail: Joyce.Wilbers@radboudumc.nl. history of a cancer, the most frequent types of *Members of the Study Group are listed in Appendix S1S1. © 2019 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology 85 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. EUROPEAN JOURNAL O F N EUROLOGY 86 J. WILBERS ET AL. previous cancer were lung (30%), brain (9%) and had died, we also collected oncological information by prostate (9%) [5]. The population of long-term cancer reviewing medical records and contacting the general survivors is growing, and several studies have reported practitioner or treating physician. The interval between on the long-term vascular complications in these cancer and stroke was calculated in years. patients [6–8]. Nevertheless, studies on the prevalence For comparison of our data, we used information and characteristics of cancer in a large cohort of from the database of The Netherlands Cancer Registry, patients presenting with ischemic stroke are lacking. which registers the most important statistics on cancer The purpose of the current study was to investigate in The Netherlands and is managed by the Netherlands the long-term prevalence of previous cancer in Comprehensive Cancer Organisation (Integraal Kanker patients diagnosed with stroke in comparison with Centrum Nederland (IKNL)). Data collected included that in the general population in The Netherlands. incidence, prevalence, survival, mortality and risk of different cancer types, as well as localization and mor- phological classification of tumors. Combining localiza- Materials and methods tion and morphology enables precise classification of From May 2007 until March 2014, we recruited par- diagnosis. The definitions used for cancer in stroke were ticipants in a prospective multicenter cohort study, in accordance with the classification of tumors used by called the String of Pearls Institute, a collaboration of The Netherlands Cancer Registry based on the 10th the eight university medical centers in The Nether- edition of the International Classification for Diseases lands. Details of this study protocol have been (ICD-10). The ICD-10 codes used were: C81–C96, C38, described previously [9]. In short, a national stroke C40–C41, C46–C49, C50, C70–C72, C73–C75, C00– database with a standardized central infrastructure C14, C30–C32, C69, C43–C44, C60–C63, C33–C34, allowed uniform data collection and storage of bioma- C45, C15–C26, C51–C58, C37, C39, C76 and C80. terials in patients presenting with a recent cerebrovas- Basal cell carcinoma and adenoma of the pituitary cular disease. For the current study, we included are not registered by The Netherlands Cancer Registry. patients with ischemic stroke or transient ischemic attack as index event. All local Medical Ethical Com- Data analysis mittees of participating hospitals approved the study. The research was performed according to the princi- Stroke characteristics (cardiovascular risk factors, ples of the Declaration of Helsinki and in accordance stroke etiology, treatment and outcome) in the patients with the Medical Research Involving Human Subjects with and without a history of cancer were compared Act and codes on ‘good use’ of clinical data and bio- after stratification for age. All cancer characteristics logical samples as developed by the Dutch Federation were separately analyzed for patients who had active of Medical Scientific Societies (http://www.wma.net/ cancer (defined as not disease free), had been cancer en/10home/index.html). All patients provided written free ≤5 years [short-term cancer-free patients (CFPs)] informed consent. and had been cancer free >5 years (long-term CFPs). We collected data on age, sex, cardiovascular risk We used Fisher’s test and chi-squared test to assess factors (smoking, hypertension, hypercholesterolemia, unadjusted differences in proportions and a t-test to diabetes mellitus), presence or a history of atrial fibril- assess differences in mean values. In order to deter- lation, previous cardiovascular events (ischemic mine if any cancer type was more common amongst stroke, transient ischemic attack, acute myocardial stroke patients, we compared the 20-year prevalence infarction and peripheral arterial disease), stroke of cancer diagnosis with the 20-year prevalence of severity by means of the National Institutes of Health diagnosis in the Dutch population for specific cancer Stroke Scale score at admission and functional out- localizations. We used data from The Netherlands come at 3 months by the modified Rankin scale score Cancer Registry to calculate the expected number of [10]. Etiology of stroke was classified according to the cases in our cohort, based on its age and sex distribu- modified Trial of Org 10172 in Acute Stroke Treat- tion. We calculated standardized prevalence ratios ment (TOAST) criteria [11]. (SPRs) by dividing the observed cancer number by In the subset of patients with a history of cancer the expected cancer number. (n = 321), we retrospectively collected information by reviewing the clinical records and contacting the general Results practitioner or treating oncological physician about the type and stage of the cancer and treatment (type of We included 2736 patients with a mean (SD) age of chemotherapy, use of angiogenesis inhibitor, RT 65 (14) years of whom 59% were men. Of these dosage and location). In those cases where the patient patients, 321 (12%) had a history of cancer. The total © 2019 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology CANCER PREVALENCE IN STROKE PATIENTS 87 Table 1 Demographics and characteristics of patients with number of cancers was 360. Patients with a history of (n = 321) and without (n = 2415) a history of cancer at the time of cancer were significantly older (mean age diagnosis of ischemic stroke 72  12 years) than patients without a history of can- cer (mean age 64  14 years) (Table 1). There were Stroke Stroke patients patients with without cancer no significant differences in stroke characteristics cancer history history between the patients with and without a history of (n = 321) (n = 2415) P cancer. The majority of strokes were caused by large (12%) (88%) value artery disease in both groups (39%). Demographics Men 186 (58) 1435 (59) 0.77 Age (years) 72  12 64  14 <0.001 Cancer characteristics Risk factors Among the 321 stroke patients with a history of can- Smoking Never 113 (38) 847 (37) 0.18 cer, 13 different types of cancer were identified. The Stopped > 6 months 123 (41) 761 (33) most common primary malignancy locations were Stopped < 6 months 8 (3) 48 (2) male genital tract (16%), breast (16%), digestive tract Current 57 (19) 637 (28) (13%), urinary tract (10%) and head and neck (9%) Hypertension 190 (59) 1271 (53) 0.85 (Table 2). A total of 53% of the patients with cancer Hypercholesterolemia 116 (37) 831 (35) 0.49 were long-term CFPs at the time of stroke. Of the Diabetes 60 (19) 376 (16) 0.86 Atrial fibrillation 53 (17) 286 (12) 0.72 short-term CFPs, 42 (26%) were treated with Alcohol use 158 (56) 1317 (61) 0.31 chemotherapy versus 15% of the long-term CFPs Past arterial events (P < 0.02). Most frequently used chemotherapy IS/TIA 98 (32) 655 (29) 0.97 included platinum-based (45%) or alkylating (33%) AMI 43 (14) 259 (11) 0.82 agents in the short-term CFPs and alkylating (65%) PAD 28 (9) 180 (8) 0.92 Stroke characteristics or antibiotic (55%) agents in the long-term CFPs. A Duration < 24 h 58 (19) 419 (18) 0.57 total of 66 (41%) of the short-term CFPs versus 82 TOAST (47%) of the long-term CFPs had received RT, most LAD 84 (39) 645 (39) 0.05 frequently for head and neck cancer (Table 3). CE 42 (19) 222 (14) In the current cohort of stroke patients, increased SVD 30 (14) 291 (18) Other 62 (28) 480 (29) SPRs were observed for cancer of the central nervous NIHSS score 4 54  5 0.94 system (CNS) [SPR, 18.2; 95% confidence interval Treatment (CI), 9.0–27.4], head and neck (SPR, 3.4; 95% CI, IV thrombolysis 44 (16) 386 (19) 0.29 2.3–4.6), lower respiratory tract (SPR, 2.4; 95% CI, Outcome at 3 months (MRS score) 0 64 (28) 589 (31) 0.20 1.5–3.3) and urinary tract (SPR, 2.1; 95% CI, 1.4–2.9) 1 64 (28) 500 (28) (Table 4). Patients with CNS cancer showed a mean 2 39 (17) 400 (22) cancer–stroke interval of 9.2 years and 40% had an 3 27 (12) 183 (10) undetermined etiology of stroke. A total of 57% of 4 19 (8) 81 (5) patients with CNS cancer had received RT with a 5 2 (1) 24 (1) 6 13 (6) 56 (3) mean (SD) dose of 55 (8) Gy. The subgroup of 23 patients with CNS cancer consisted mostly of glial Data are given as n (%, complete case analysis) and mean  SD. tumors (n = 8) and meningioma (n = 8) AMI, acute myocardial infarct; CE, cardioembolism; IS, ischemic (Appendix S2). Patients with head and neck cancer stroke; IV, intravenous; LAD, large artery disease; MRS, modified had a mean cancer–stroke interval of 7.2 years, Rankin scale; NIHSS, National Institutes of Health Stroke Scale; PAD, peripheral arterial disease; SVD, small vessel disease; TIA, TOAST classification showed mostly large artery dis- transient ischemic attack; TOAST, Trial of Org 10172 in Acute ease (71%) and 44% were current smokers. Patients Stroke Treatment. P value for difference adjusted for age. with lower respiratory tract cancer had a mean cancer–stroke interval of 6 years and 77% were cur- stroke and cancer characteristics, and compares rent or former smokers. Patients with urinary tract these with those in the general population. As can- cancer had a mean cancer–stroke interval of 7.4 years cer survival improves, it is increasingly relevant to and 62% were current or former smokers. have knowledge of and to pay attention to vascular complications in patients with cancer. It is impor- Discussion tant to define types of cancer associated with stroke risk and their specific risk factors. These findings The current study is the first and largest multicenter are useful in the development of prevention study among stroke patients that combines patient, © 2019 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology 88 J. WILBERS ET AL. Table 2 Absolute and relative frequencies of prevalent cancer subtypes at the time of ischemic stroke diagnosis Type of cancer Total (n = 360) Cancer free ≤ 5 years (n = 171) Cancer free > 5 years (n = 189) Male genital tract 59 (16) 36 (21) 23 (12) Breast 57 (16) 16 (9) 41 (22) Digestive tract 48 (13) 23 (14) 25 (13) Urinary tract 35 (10) 19 (11) 16 (9) Head and neck 33 (9) 14 (8) 19 (10) Blood, lymph and bone marrow 28 (8) 14 (8) 14 (7) Lower respiratory tract 27 (8) 15 (9) 12 (6) Skin 26 (7) 10 (6) 16 (9) Central nervous system 20 (6) 16 (9) 4 (2) Female genital tract 15 (4) 4 (2) 11 (6) Endocrine 7 (2) 3 (2) 4 (2) Bone and soft tissue 4 (1) 1 (1) 3 (2) Eye and orbit 1 (0) 0 (0) 1 (1) Data are expressed as absolute n (%). guidelines for patients who survive cancer. The We did not find an increased prevalence of stomach prevalence of cancer was higher in ischemic stroke cancer; however, cancer type distributions differ patients than in the general population. In particu- around the world. The purpose of the current study lar, CNS, head and neck, lower respiratory tract was to investigate the long-term prevalence of previ- and urinary tract cancers were more prevalent in ous cancer in stroke patients in comparison with the ischemic stroke patients than in the age- and sex- general population. We found increased prevalence matched general population. Stroke etiology and ratios of cancer types more associated with long-term outcome did not differ between ischemic stroke survival. Underlying mechanisms for increased risk of patients with and without a cancer history. stroke in these long-term survivors are long-term RT- The strongly increased SPR of CNS cancer in induced vasculopathy or shared risk factors like smok- stroke patients has never been described before. The ing. In contrast, other studies evaluated the more underlying pathology might partly be explained by a short-term risk of stroke in patients with active cancer long-term RT-induced intracranial vasculopathy. [4,18–21]. Increased risk of stroke was reported mostly There are no previous reports of increased stroke risk in lung, pancreatic and colorectal cancers. In these in patients with meningioma. The association of patients, cancer may also have a causal relationship glioblastoma multiforme and ischemic strokes might with stroke by inducing a hypercoagulable state, non- be explained by post-operative complications, late bacterial thrombotic endocarditis and compression of complications of RT, a hypercoagulable state induced blood vessels by the tumor. The discrepancy in cancer by the tumor or vessel occlusion that is caused by an types associated with stroke in long-term survivors adjacent tumor [12,13]. In head and neck cancer, versus patients with active cancer can be explained by post-radiation vasculopathy of the carotid artery is different underlying associated mechanisms. The study the most likely and best-known link with an increased of Selvik et al. of cancer prevalence in stroke patients risk of stroke [7,14]. The relatively high percentage of in Norway [22] was similar to our study setting. In a RT in this type of cancer and the relatively long mean cohort of 1456 ischemic stroke patients, 15.7% of the latency period (9 years) between cancer and stroke patients had one or more cancer diagnosis before support this association. Furthermore, head and neck, stroke. This prevalence of cancer in stroke patients lower respiratory and urinary tract cancer, and stroke was higher than the prevalence of cancer in the gen- have similar risk factors, in particular smoking. Most eral population. These results are similar to the results patients treated with chemotherapy had received plat- of the current study. The added value of the current inum-based or alkylating therapy, which are associ- study is the larger stroke cohort and, more impor- ated with a known increased risk of stroke [15]. The tantly, the reporting of SPRs of different cancer types most frequent cancer types in previous smaller retro- compared with the general population instead of the spective studies in stroke patients included urogenital, reporting of only prevalence of cancer types, which breast, gastrointestinal, hematological and lung [16]. makes comparison of the prevalence of different can- A high frequency of stomach cancer was observed in cer types with the general population more difficult. a retrospective case-control study in stroke patients in Furthermore, we found that stroke characteristics Korea [17]. were not different between patients with or without a © 2019 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology CANCER PREVALENCE IN STROKE PATIENTS 89 Table 3 Characteristics of cancer treatment in an ischemic stroke population Treatment characteristic Total (n = 360) Cancer free ≤ 5 years (n = 171) Cancer free >5 years (n = 189) P value Chemotherapy 68 (20) 42 (26) 26 (15) 0.02 Alkylating 26 (44) 13 (33) 13 (65) 0.04 Platinum-based 21 (36) 17 (45) 4 (20) 0.12 Antibiotic 17 (29) 6 (15) 11 (55) 0.004 Topoisomerase inhibitor 12 (21) 9 (24) 3 (16) 0.73 Antimetabolite 9 (16) 7 (18) 2 (11) 0.70 Antimitotic 9 (16) 3 (8) 6 (30) 0.07 Methotrexate 6 (11) 3 (8) 3 (16) 0.65 Local 7 (13) 4 (11) 3 (16) 0.68 Other 20 (34) 14 (36) 6 (30) 0.87 Other systemic treatments Rituximab 7 (12) 6 (16) 1 (5) 0.48 Tyrosine kinase inhibitor 3 (5) 3 (8) 0 (0) 0.53 Angiogenesis inhibitor 7 (2) 5 (3) 2 (1) 0.39 RT 148 (44) 66 (41) 82 (47) 0.29 Location of RT Head or neck 54 (37) 25 (39) 29 (35) 0.06 Chest 41 (28) 12 (19) 29 (35) Other 52 (35) 28 (43) 24 (29) Dose (Gy) Head or neck 52  15 53  16 50  15 0.51 Chest 51  11 52  14 50  9 0.69 Other 50  30 40  24 62  33 0.08 Data are expressed as n (%) (complete case analysis) and mean  SD. Valid percentages do not add up to 100% due to overlap and multiple treatments. P value for difference between cancer free ≤ 5 years and cancer free > 5 years by chi-squared test and for differences in radiother- apy (RT) dose by independent sample t-test. Table 4 Standardized 20-year prevalence ratio of cancer subtypes in ischemic stroke patients Type of cancer Observed number Expected number SPR 95% CI Male genital tract 56 54 1.0 0.8–1.3 Breast 43 42 1.0 0.7–1.3 Digestive tract 38 46 0.8 0.6–1.1 Urinary tract 31 15 2.1 1.4–2.9 Head and neck 29 9 3.4 2.3–4.6 Blood, lymph and bone marrow 23 18 1.3 0.8–1.8 Lower respiratory tract 26 11 2.4 1.5–3.3 Skin 21 38 0.6 0.3–0.8 Central nervous system 15 1 18.2 9.0–27.4 Female genital tract 5 12 0.4 NA Bone and soft tissue 2 2 1.1 NA Endocrine 4 1 2.7 NA Any cancer 273 238 1.2 1.0–1.3 Expected number calculated from the age-specific 20-year prevalence in the Dutch population (source: Dutch Cancer Registration, www.cijfe rsoverkanker.nl). Cancer diagnosis > 20 years before 2011 was excluded in these analyses. CI, confidence interval; NA, not applicable; SPR, standardized prevalence ratio. SPR for male genital tract, female genital tract and breast cancer was calculated for men only and women only, respectively. 95% CI for cancer types with low prevalence (i.e. <5 cases) could not be calculated. cancer history, which is in line with previous smaller distributions are different over the world and depend retrospective analyses [16,17,23]. on age and sex, it was important that we were able to Our study is the first and largest multicenter study compare the prevalence of the different cancer types in stroke patients in The Netherlands that combined in our stroke cohort with that from the same source patient, stroke and cancer characteristics. Further- population, stratified by age and sex. more, this study compared these characteristics with Our study has some limitations. Patients with a his- those in the general population. As cancer type tory of cancer potentially have a higher likelihood of © 2019 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology 90 J. WILBERS ET AL. being diagnosed with stroke due to long-term surveil- Disclosure of conflicts of interest lance with lower threshold to perform more extensive The authors declare no financial or other conflicts of evaluations. However, we did not observe differences interest. The work described in this study was carried in stroke subtypes or severity between patients with out in the context of the Parelsnoer Institute. PSI is and without a cancer history. If this bias had part of and funded by the Dutch Federation of occurred one would expect more relatively mild University Medical Centers and has received initial strokes in those with a cancer history. Furthermore, funding from the Dutch Government (from 2007 to patients with a history of cancer could have been 2011). more often referred to university medical centers because of their cancer history. This is not very likely because in The Netherlands almost all hospitals pro- Supporting Information vide acute stroke care and patients are referred to the Additional Supporting Information may be found in nearest hospital. Furthermore, we did not observe dif- the online version of this article: ferences between participating hospitals with large specialized oncology departments and those without. Appendix S1. Study group. The retrospective identification and verification of Appendix S2. Characteristics of patients with central cancer cases may have resulted in some misclassifica- nervous system cancer. tion. However, it is unlikely that cancer is under-re- ported by the patients themselves because of the References impact of this disease. Furthermore, the systematic 1. 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European Journal of Neurology – Pubmed Central

Published: Jul 29, 2019

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