Author: Dr Nicolas Martinez-Majander

Affiliation: Clinical Neurosciences, Department of Neurology, University of Helsinki and Department of Neurology, Helsinki University Hospital, Finland

According to Word Health Organization (WHO), noncommunicable diseases, such as cardiovascular diseases, cancer, and chronic obstructive pulmonary disease account for 80% of deaths in the European Region. Particularly, diseases of the circulatory system (e.g. stroke) are the most important cause of premature death in Europe, accounting for nearly 50% of the total.

Up to 10% of ischemic stroke patients have also comorbid cancer.1 Potential mechanisms between cancer and ischemic stroke are still partially unclear, but include abnormalities in the coagulation system, in platelets, and in fibrinolytic pathways, as well as endothelium dysfunction and abnormalities in turbulence in abnormal blood vessels. Cancer can also lead to marantic (non-bacterial) endocarditis, anemia, mechanical compression of critical vessels, tumor embolism, and cerebral venous thrombosis.2,3 Importantly, active cancer can contribute to early neurological deterioration, higher in-hospital post-stroke mortality, and substantial short-term risk of stroke recurrence and other thromboembolic events.4,5,6

Cancers related to smoking are particularly associated with increased risk of stroke, but other malignancies such as lymphoma and central nervous system cancer, could be also associated with stroke.7,8 In patients with stroke of unknown cause you should particularly be aware of  lung, pancreatic, breast, stomach and colon cancers, as these are most likely to be associated with stroke.

Regarding to stroke etiologic subtype, cryptogenic strokes especially in elderly patients, perhaps with an embolic pattern (brain imaging might show multiple lesions in multiple arterial territories), should raise the suspicion of occult cancer as a possible underlying etiology. 9

What about hemorrhagic strokes? In a registry-based study of 208 patients with intracerebral or subarachnoidal hemorrhages, 68% had solid tumors, while 16% had primary brain tumors and 16% hematopoietic tumors. Of all the patients in this study, up to 44% had a known primary or metastatic brain tumor at the time of hemorrhage.  Overall, patients had less frequently conventional risk factors such as hypertension, and the prognosis was quite poor – but still comparable to intracranial hemorrhage in general population.10 The Danish study by Anderssen et al reported that as with ischemic stroke, the most frequent cancer types associated with hemorrhagic stroke are also smoking-related.8

When treating patients with cancer-related ischemic stroke, the most frequent question concerns optimal antithrombotic therapy in the future. An excellent review by Navi et al summarizes the scarce data on the topic so far.3 Although anticoagulation, especially low-molecular-weight heparins and more recently NOACs have been recommended for secondary prevention, the data so far comes mainly from venous thromboembolism trials.11 Navi et al also showed in their TEACH trial pilot that in 20 patients with active cancer-related ischemic stroke randomized either to enoxaparin or aspirin, there were no difference in the relevant outcomes (major bleeding, thromboembolic events, and survival).12 Still, only few studies have addressed the issue of superiority of e.g. direct oral anticoagulant compared to antiplatelets and large prospective randomized trials are needed.

In conclusion, the association between active cancer and stroke should be kept in mind, especially in cryptogenic stroke with embolic pattern. However, further studies on optimal antithrombotic treatment strategies in cancer-related stroke are still needed.

 

References:

  1. Navi BB, Reiner AS, Kamel H, et al. Association between incident cancer and subsequent stroke. Ann Neurol 2015;77:291–300.
  2. Lip GY, Chin BS, Blann AD. Cancer and the prothrombotic state. Lancet Oncol 2002;3:27-34.
  3. Navi BB, Iadecola C. Ischemic stroke in cancer patients: A review of an underappreciated pathology. Ann Neurol 2018;83:873-883.
  4. Nam KW, Kim CK, Kim TJ, An SJ, Oh K, Mo H, et al. Predictors of 30-day mortality and the risk of recurrent systemic thromboembolism in cancer patients suffering acute ischemic stroke. PLoS One 2017;12:e0172793.
  5. Zhang YY, Cordato D, Shen Q, Sheng AZ, Hung WT, Chan DK. Risk factor, pattern, etiology and outcome in ischemic stroke patients with cancer: a nested case-control study. Cerebrovasc Dis 2007;23(2-3):181-187.
  6. Navi BB, Singer S, Merkler AE, Cheng NT, Stone JB, Kamel H, et al. Recurrent thromboembolic events after ischemic stroke in patients with cancer. Neurology 2014;83:26-33.
  7. Schwarzbach CJ, Schaefer A, Ebert A, Held V, Bolognese M, Kablau M, et al. Stroke and cancer: the importance of cancer-associated hypercoagulation as a possible stroke etiology. Stroke 2012;43:3029-3034.
  8. Andersen KK, Olsen TS. Risk of Ischemic and Hemorrhagic Strokes in Occult and Manifest Cancers. Stroke 2018;49:1585-1592.
  9. Kim SG, Hong JM, Kim HY, Lee J, Chung PW, Park KY, et al. Ischemic stroke in cancer patients with and without conventional mechanisms: a multicenter study in Korea. Stroke 2010;41:798-801.
  10. Navi BB, Reichman JS, Berlin D, Reiner AS, Panageas KS, Segal AZ, et al. Intracerebral and subarachnoid hemorrhage in patients with cancer. Neurology 2010;74:494-501.
  11. Raskob GE, van Es N, Verhamme P, Carrier M, Di Nisio M, Garcia D, et al. Edoxaban for the Treatment of Cancer-Associated Venous Thromboembolism. N Engl J Med 2018 Feb 15;378(7):615-624.
  12. Navi BB, Marshall RS, Bobrow D, Singer S, Stone JB, DeSancho MT, et al. Enoxaparin vs Aspirin in Patients With Cancer and Ischemic Stroke: The TEACH Pilot Randomized Clinical Trial. JAMA Neurol 2018;75:379-381.