Ischemic stroke in a patient with EGFR‐mutated non–small‐cell lung cancer after treatment with ramucirumab

Abstract Vascular endothelial growth factor (VEGF) inhibitors have been widely investigated in the last 10 years, with particular attention paid to their adverse effects because of their efficacy in improving cancer patient survival. Previous research primarily focused on the monoclonal anti‐vascular endothelial growth factor antibody bevacizumab and its adverse outcomes. Reports show a higher risk of ischemic stroke, one of the most concerning clinically relevant events, after treatment with bevacizumab. However, few studies have examined the relationship between anti‐VEGF receptor 2 monoclonal antibody ramucirumab and its adverse events. This article presents the case of a non–small‐cell lung cancer patient who experienced a new ischemic stroke after treatment with ramucirumab. The findings suggest that further studies may be necessary to investigate the relationship between ramucirumab and the risk of ischemic stroke.


INTRODUCTION
Research interest is growing in various adverse events of anti-vascular endothelial growth factor (anti-VEGF) medication because of its wide use and efficacy in improving the survival of cancer patients. [1][2][3] Myocardial infarction, hypertension, and new-onset proteinuria have been reported as adverse events. 4 Ischemic stroke is also one of the most concerning clinically relevant adverse events. [4][5][6][7][8][9] However, the relationship between anti-VEGF agents and the incidence of cerebral ischemia is still controversial. [4][5][6][7][8][9] Bevacizumab and ramucirumab are vascular endothelial growth factor (VEGF) signaling pathway inhibitors and are indicated in the treatment of non-small-cell lung cancer (NSCLC) patients. 10,11 Although treatment with bevacizumab has been reported to increase the risk of cerebral ischemia, 9 stroke cases have rarely been mentioned after the use of ramucirumab. To our knowledge, only one case has been reported of an 82-year-old male with metastatic gastric cancer suffering from multifocal ischemic stroke after treatment with four doses of ramucirumab. 12 We present the first case of an ischemic stroke in an NSCLC patient after treatment with ramucirumab.

CASE REPORT
A 67-year-old female diagnosed with NSCLC harboring the EGFR-L858R mutation, with liver, spine, right rib, bilateral adrenal gland, and brain metastases (Figure 1), visited our chest outpatient department because of frequent dizziness and falls. Her past medical history included type II diabetes mellitus with metformin control and asthma for 30 years. She initially received targeted therapy with second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) plus ramucirumab for treatment. After receiving ramucirumab for approximately 1.5 months, she began suffering from persistent dizziness and frequent falls.
On examination, she appeared chronically ill, but was still alert. She could only say a single word. Her vital signs were stable. A physical examination showed medial side deviation when performing an extraocular muscle function test (the provider moved the object to the left side), poor gag reflex, decreased upper limb muscle power (2 points), mild flattening of the left nasolabial fold, and a positive Babinski sign on the left side. Laboratory tests revealed leukocytosis with neutrophil predominance (WBC, 17,600/μL; neutrophil, 86.8%). Repeated brain magnetic resonance imaging performed because of suspected progression of the disease disclosed partial remission of diffuse intracranial metastatic tumors with residual tumors in the midbrain, cerebellum, bilateral basal ganglia, and bilateral hemispheres of the cerebrum, but suspected diffuse embolic acute infarctions in the left thalamus, bilateral basal ganglia, bilateral corona radiata, and bilateral temporal, bilateral frontal, bilateral parietal, and bilateral occipital lobes (Figure 2). The electrocardiogram showed no arrhythmia. Transcranial Doppler sonography results were within normal limits except for very mild atherosclerotic changes in the bilateral bulb. Echocardiography revealed preserved left and right ventricular contractility with normal chamber size and no abnormality in left ventricular regional wall motion. The patient then received rehabilitation and acupuncture for post-stroke care.

DISCUSSION
To our knowledge, this is the first case report detailing a new-onset ischemic stroke in an NSCLC patient after ramucirumab treatment. A previous case report described a patient with metastatic gastric cancer who suffered from an ischemic stroke after treatment with ramucirumab. 12 However, these cases are rarely reported. Bevacizumab has been well investigated in previous studies that discussed the relationship between angiogenesis inhibitors and the risk of arterial thromboembolism (ATE). In a meta-analysis that evaluated cardiovascular adverse effects in cancer patients after treatment with bevacizumab, Totzek et al. 9 reported a higher risk of developing cerebral ischemia in the bevacizumab group (relative risk [RR], 3.11; 95% CI, 1.46-6.65; p = 0.003). Another meta-analysis of 77 Phase III trials that primarily included bevacizumab also showed a higher odds ratio for ATE (1.52 [95% CI, 1.17-1.98]). 5 Nevertheless, only a few studies have targeted ramucirumab for evaluation. A report that examined the incidence of adverse events, F I G U R E 1 T 2 -weighted fluid attenuated inversion recovery (FLAIR) brain magnetic resonance imaging for initial cancer status evaluation revealed multiple hyperintense lesions in the bilateral hemispheres and suspected non-small-cell lung cancer with brain metastasis.
F I G U R E 2 Sequential diffusion-weighted imaging (a) and the apparent diffusion coefficient (b) of the brain magnetic resonance imaging showed an increased multifocal signal because of diffusion restriction and a corresponding decrease in signal intensity, respectively. The result is compatible with ischemic stroke-related cytotoxic edema. possibly because of VEGF signaling pathway inhibition by ramucirumab, revealed 38 (1.4%) and 40 (1.8%) cases of all-grade ATE in the ramucirumab and control arms, respectively (RR, 0.8; 95% CI, 0.5-1.3). 6 However, patients who had a cerebrovascular accident or transient ischemic attack within 6 to 12 months before randomization were excluded in five of the six trials included in the study, and therefore, whether or not patients were better selected to reduce the risk of ATE is unknown. 6 In our case, the patient had long-term diabetes mellitus, but the condition was well controlled by medication. Her cancer status was a partial response of tumor shrinkage noted by imaging. Although both are considered risk factors for stroke, the conditions were relatively stable; therefore, their effects might have been slight.
In conclusion, we report a new-onset ischemic stroke in an NSCLC patient after treatment with ramucirumab. The previous study targeting ramucirumab may be limited because of patient inclusion criteria. 6 Therefore, further extensive studies are necessary to investigate the relationship between ramucirumab and the risk of ischemic stroke.

ACKNOWLEDGMENTS
We are extremely grateful to all colleagues who contributed to this case report. We thank anonymous reviewers and the editor for their comments. This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.