Journal of the Neurological Sciences 325 (2013) 100–102
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Intravenous Alteplase for acute ischemic stroke in patients with current malignant neoplasm Manuel Cappellari ⁎, Monica Carletti, Nicola Micheletti, Giampaolo Tomelleri, Domenico Ajena, Giuseppe Moretto, Paolo Bovi SSO Stroke Unit, U.O. Neurologia d.O., DAI di Neuroscienze, Azienda Ospedaliera Universitaria Integrata, Verona, Italy
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Article history: Received 12 November 2012 Received in revised form 7 December 2012 Accepted 10 December 2012 Available online 11 January 2013 Keywords: Intravenous thrombolysis Acute ischemic stroke Cancer
a b s t r a c t Background: The current European license for Alteplase in acute ischemic stroke excludes the patients who have neoplasm with increased bleeding, but this criterion is not clearly defined. The aim of the present study is to assess whether intravenous (IV) thrombolysis is safe and effective in patients with current non-malignant neoplasm in absence of metastatic disease or other additional risk factors of bleeding. Methods: We reviewed the clinical characteristics of 11 thrombolysed patients with current malignant neoplasm. We decided to treat only patients who did not have one or more of the following additional risk factors of bleeding: metastatic malignant disease; recent bleeding; documented hemorrhagic diathesis, also including baseline normal platelet count, activated partial thromboplastin time and prothrombin time value; and anticoagulant treatment on admission. Results: Cancer was diagnosed before IV thrombolysis in 9 patients, while non-metastatic malignant disease was incidentally detected after IV thrombolysis in 2 patients. None of the patients showed severe hemorrhagic complications. At 7 days, all patients that showed a reduction of 4 points or more in the National Institutes of Health Stroke Scale from baseline were asymptomatic. At 3 months, functional outcome was favorable in 7 (73%) patients. Conclusions: Our experience suggests that IV thrombolysis does not appear to increase the risk of hemorrhagic complications in current non-metastatic cancer patients in absence of additional risk factors of bleeding. In addition, these patients showed clinical improvement after IV thrombolysis, although replication of our findings in a randomized controlled trial is required to confirm our results. © 2012 Elsevier B.V. All rights reserved.
1. Introduction
2. Methods
Thrombolysis with intravenous (IV) Alteplase is the only currently approved therapy for acute ischemic stroke. Conversely to current American Heart Association guidelines [1], European Alteplase license excludes the patients who have neoplasm with increased bleeding, but this criterion is not clearly defined [2]. Since ischemic stroke is a relatively common complication in patients with cancer, in the clinical practice, many cancer patients receive the treatment with IV Alteplase under the discretion of physician. The aim of the present study is to assess whether IV thrombolysis is safe and effective in patients with current non-malignant neoplasm in absence of metastatic disease or other additional risk factors of bleeding.
We reviewed the clinical characteristics of 11 patients with current malignant neoplasm, from consecutive series of 485 acute ischemic stroke admitted to our Stroke Unit, from December 2004 to June 2012, receiving IV thrombolysis after informed consent. Patients with current malignant neoplasm were those who had a recent diagnosis of cancer, receiving or awaiting treatment, or those in which cancer was not known before thrombolysis. Since current malignant neoplasm may potentially have an increased risk of bleeding after IV thrombolysis, we decided to treat only patients who did not have one or more of the following additional risk factors of bleeding: metastatic malignant disease; recent bleeding; documented hemorrhagic diathesis, also including baseline normal platelet count, activated partial thromboplastin time and prothrombin time value; and anticoagulant treatment on admission.
⁎ Corresponding author at: SSO Stroke Unit, U.O. Neurologia d.O., DAI di Neuroscienze, Azienda Ospedaliera Universitaria Integrata, Piazzale A. Stefani 1, 37126 Verona, Italy. Tel.: + 39 3397978357; fax: + 39 045 8122804. E-mail address:
[email protected] (M. Cappellari). 0022-510X/$ – see front matter © 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jns.2012.12.008
3. Results Table 1 shows the clinical characteristics of the cancer patients treated with IV Alteplase.
Table 1 Clinical characteristics of the patients. Case and site of cancer
Baseline data NIHSS score CT sign of current infarct MCA hyperdensity Blood glucose, mg/dL SBP, mm Hg DBP, mm Hg OCSP classification TOAST classification Outcome measures NIHSS score at 24 h NIHSS score at 7 days Severe hemorrhagic complications after IV rt-PA mRS score at 3 months
No. 2 (Colon)
No. 3 (Tonsil)
No. 4 (Stomach) No. 5 (Larynx)
No. 6 (Prostate)
No. 7 (Breast)
No. 8 (Breast)
No. 9 (Tonsil)
No. 10 (Lung)
No. 11 (Colon)
84 No 0 175
63 Yes 0 100
59 Yes 0 270
81 Yes 0 190
67 Yes 1 155
75 Yes 1 168
62 No 0 170
84 No 0 175
80 Yes 0 170
73 No 0 122
70 Yes 0 225
Yes No No No No No
No No No No No No
No No No No No No
Yes No No No No No
No No No No No No
Yes Yes No No Yes No
No No No No Yes No
Yes No Yes No No No
Yes Yes No No No No
Yes No No Yes No No
Yes Yes No No No No
No
No
No
No
No
No
No
No
Yes
No
No
Yes No No Yes No No Surgery + Surgery + Surgery Chemotherapy Chemotherapy
Yes Yes Surgery
No No Surgery + Radiotherapy
Yes Yes No
No Yes Surgery + Chemotherapy
Yes Yes No
Yes Yes No
Yes Yes No
No Yes No
10 No
18 No
14 No
7 No
14 No
14 No
7 Yes
4 No
1 No
7 No
20 No
No 148 156 74 PACI Undetermined etiology
No 88 144 103 TACI Undetermined etiology
No 128 130 83 TACI Large-artery atherosclerosis
No 196 133 55 PACI Cardioembolism
No 92 125 65 TACI Large-artery atherosclerosis
No 142 185 90 TACI Cardioembolism
No 135 169 75 PACI Cardioembolism
No 169 170 70 POCI Cardioembolism
No 234 163 93 POCI Cardioembolism
No 124 125 70 PACI Undetermined etiology
No 76 161 77 TACI Cardioembolism
1 1 No
15 14 No
5 4 No
7 2 No
18 10 No
8 1 No
6 2 No
1 0 No
0 0 No
2 0 No
2 0 No
3
5
2
1
4
1
1
0
0
0
0
M. Cappellari et al. / Journal of the Neurological Sciences 325 (2013) 100–102
Demographic Age, years Sex, males Pre-stroke mRS OTT time for IV rt-PA Vascular risk factors Hypertension Diabetes mellitus Hypercholesterolemia Current smoking Atrial fibrillation Prior stroke >3 months Congestive heart failure Pre-stroke therapy Antiplatelet Antihypertensive Cancer treatment
No. 1 (Stomach)
Abbreviations: mRS=modified Rankin Scale; OTT=onset to treatment; IV=intravenous; rt-PA=recombinant tissue plasminogen activator; NIHSS=National Institutes of Health Stroke Scale; CT=computed tomography; MCA=middle cerebral artery; SBP=systolic blood pressure; DBP=diastolic blood pressure; OCSP=Oxford Community Stroke Project; TOAST=Trial of Org 10172 in Acute Stroke Treatment.
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M. Cappellari et al. / Journal of the Neurological Sciences 325 (2013) 100–102
Non-metastatic cancer was diagnosed before IV thrombolysis in 9 patients, while non-metastatic malignant disease was incidentally detected after IV thrombolysis in the patient nos. 10 and 11. During hospitalization, the first patient performed routine chest x-ray control and successive bronchoscopic biopsy which established a non-small cell lung cancer. Because of a moderate decrease of serum hemoglobin level two days after IV thrombolysis, the second patient performed a colon endoscopic biopsy that detected a sigma cancer. In our series, the mean age of the patients was 72.5 ±8.8 years. All patients were asymptomatic or without significant disability before stroke. The median National Institutes of Health Stroke Scale (NIHSS) score was 10 (range 1 to 20). According to Oxford Community Stroke Project (OCSP) classification, 5 (45%) patients were defined as total anterior circulation infarcts [3]. After IV thrombolysis, none of the patients showed severe hemorrhagic complications, including symptomatic intracerebral hemorrhage according to Safe Implementation of Thrombolysis in Stroke-Monitoring Study and European Cooperative Acute Stroke Study III definition [4,5], and major localized or systemic bleeding. At 7 days, all patients showed a reduction of 4 points or more in the NIHSS from baseline or were asymptomatic. At 3 months, functional outcome was favorable (modified Rankin Scale ≤ 2) in 8 (73%) patients.
urgent surgery. Screening for malignant diseases is not required before IV thrombolysis in patients without cancer anamnesis. The results of our report should be interpreted with caution because of the limited sample size and retrospective report design. A limitation might be the lack of follow-up oncologic assessment. Despite these limitations, our experience suggests that IV thrombolysis does not appear to increase the risk of hemorrhagic complications in current non-metastatic cancer patients in absence of additional risk factors of bleeding. In addition, these patients showed clinical improvement after IV thrombolysis, although replication of our findings in a randomized controlled trial is required to confirm our results. The corresponding author takes full responsibility for the data, the analyses and interpretation, and the conduct of the research. The corresponding author has full access to all of the data. The material submitted to Journal of the Neurological Sciences is not under review at any other publication. All authors have no financial interests to disclose. All authors have seen and agree with the contents of the manuscript and the submission is not under review at any other publication.
Conflict of interest The authors have no conflict of interest to declare.
4. Discussion This is the largest series of IV thrombolysed patients with current non-metastatic malignant disease. To date, knowledge about the safety and efficacy of thrombolytic treatment in patients with neoplasm is anecdotal [6–8]. In fact, these patients were generally excluded from the majority of clinical trials because the concomitant morbidity could have influenced the stroke outcome. Recent study showed higher risk of mortality in IV and/or intra-arterial thrombolysed patients with current neoplasm. However, this was attributable to withdrawal of care due to comorbid medical conditions, including metastatic disease, but not to hemorrhagic complications [7]. Our report shows that thrombolytic treatment in patients with current non-metastatic cancer and without additional bleeding risk does not increase bleeding complications, but rather improves neurological and functional outcome. Cancer is one of the major acquired prothrombotic states associated with increased risk for stroke [9]. According to Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria [10], this could explain undetermined etiology of stroke in about one third of our patients. Although local tumor invasion of blood vessels or generalized bleeding diathesis may increase the risk of bleeding in some patients with malignant disease, prothrombotic mechanisms are predominant during the acute phase of ischemic stroke. This could explain also the low risk of cerebral and systemic hemorrhage after IV thrombolysis in our selected cancer patients. Only patient no. 11 presented localized bleeding, but colon cancer was undetected before IV Alteplase. However, this complication was not significant because the patient did not require blood transfusion or
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