This is the first population-based study to determine the risk of new onset ischemic stroke after an ovarian cancer diagnosis. Our data revealed an increased risk of developing ischemic stroke with an adjusted HR of 1.49 among patients with ovarian cancer. Significant risk factors for ischemic stroke included age ≥50 years, diabetes mellitus, hypertension, and chemotherapy treatment.
Up to 40% of stroke cases in cancer are cryptogenic related, possibly induced by the underlying malignancy
. For cancer patients, RRs of developing venous thrombosis of four- to seven-fold have been reported compared with matched controls
. However, cancer is a broad disease and different types of cancer may have different risks. Generally, pancreas, brain, lung, and ovarian cancers have been associated with the higher risks of developing venous thrombosis
. In addition, the presence of disseminated intravascular coagulation in patients with ovarian cancer may indicate a hypercoagulative status
. One direct evidence for the hypercoagulative state is the frequently overexpressed tissue factor in ovarian cancer tissue, which could activate the extrinsic coagulation cascade and cause thrombolic events in ovarian cancer patients
Although the temporal-causal relationship between ovarian cancer progression and hypercoagulation is unknown, high levels of coagulation factors and associated regulatory proteins have been observed in ovarian cancer patients
[15, 16]. Increased levels of circulating mucinous material produced by ovarian tumors might play a role in intravascular hypercoagulation and hyperviscosity
. Together, these findings suggest that a subgroup of ovarian cancer patients may have distinct coagulopathies, making these patients vulnerable for specific vascular events, including ischemic stroke. These findings may also explain why ovarian cancer survivors in our study, especially younger patients who had no established conventional stroke risk factors, possessed a higher risk of subsequent ischemic stroke.
The most well-known and medically important (that is, treatable) risk factors for ischemic stroke include hypertension, diabetes mellitus, dyslipidemia, smoking, and obesity
. Although lifestyle and obesity were not included in the present analysis, some epidemiological studies have demonstrated that hypertension and diabetes are significant risk factors for stroke in several cancers
[19, 20]. Our multivariate analyses revealed a similar result, with additional significant risk factors, including age ≥50 years old and chemotherapy treatment. These results suggest that conventional stroke risk factors remain important in the pathogenesis of stroke in ovarian cancer patients.
Our study showed that ovarian cancer patients receiving chemotherapy, particularly platinum-based regimens, might have an additionally increased stroke risk. This effect was insignificant in non-platinum-based regimens. In prior studies, chemotherapy-associated increased stroke was observed in patients with head-and-neck cancer
[19, 21], breast cancer
, and urothelial carcinoma
. While the mechanism is still uncertain, some suggested pathophysiologies are associated with increased fibrinopeptide A and decreased fibrinolytic activity
, elevated plasma von Willebrand factor
, hypomagnesium-associated vascular spasm
[26, 27], endothelial injury
[28, 29], and mononuclear cell-mediated platelet activation
. Moreover, Li et al. demonstrated that platinum in a chemotherapy regimen, which is also commonly used for treating ovarian cancer patients, may increase the risk of ischemic stroke among cancer patients
. Cerebral infarction after cisplatin-based chemotherapy in ovarian cancer patients has also been reported previously
[32, 33]. A meta-analysis of 38 randomized phase II and III trials showed that cancer patients who received cisplatin-based chemotherapy demonstrated a dose-dependently increased risk (RR 1.67, 95% CI, 1.25 to 2.23; P = 0.01) of thromboembolism compared with patients who received a non-cisplatin-based regimen
. More research is needed to clarify the role of chemotherapy in the relationship of ovarian cancer and subsequent ischemic stroke, as well as to determine whether it is necessary to use a prophylactic antiplatelet agent in high-risk patients during the chemotherapy period.
Our study revealed that ovarian cancer patients appeared to have a higher risk of stroke soon after cancer diagnosis, and the increased risk persisted throughout the follow-up period. A similar phenomenon was also observed in survivors of head-and-neck cancer
[19, 21], cervical cancer
, breast cancer
, and Hodgkin lymphoma
. The stroke risk imposed by ovarian cancer seemed to be more prominent in people of younger age, with adjusted HRs of 2.28 and 1.33 in the age groups of <50 years and ≥50 years, respectively. These findings suggest that, with increasing age, the age factor becomes more important than cancer as a risk factor of stroke.
This study has several limitations. First, lifestyle variables and behavioral factors, such as tobacco and alcohol use, body mass index, dietary habits, and biochemistry profiles including serum D-dimer level and disseminated intravascular coagulation profiles, were not available in the claims data of the Taiwan NHI. Second, cancer staging and histology were not available in this database, and their association with ischemic stroke could not be identified. Finally, information on the cause of death was not available; consequently, we cannot determine the impact of stroke on cancer-related mortality. Despite these limitations, our study was based on a nationwide, population-based database that could identify all cases of ovarian cancer and ischemic stroke in the study period. The large sample size in our study contributed to substantial statistical power and revealed a clear association between ovarian cancer and ischemic stroke, with subtle statistically significant differences between the two cohorts.