Sunitinib, a tyrosine kinase inhibitor, extends the survival of patients with chromophobe metastatic renal cell and gastric stromal tumours. In metastatic renal cell carcinoma, sunitinib is associated with a greater progression-free survival and patient reported quality of life over interferon alpha.1
Tyrosine kinases are often mutated or over expressed in many cancer types and the advent of small molecule inhibitors such as sunitinib have improved the tolerability of chemotherapy for many patients. Sunitinib inhibits a number of target receptors and molecules including VEGF receptors and platelet derived growth factors, colony stimulating factor-1, and FMS-like tyrosine kinase-3.2
These multi-modal actions affect angiogenesis and may impair maintenance or even cause regression of normal organ vasculature; they have been associated with bleeding and also affect normal cell tyrosine kinases, resulting in hypothyroidism3
(as in this case) and possible cardiac dysfunction. Recent reports have raised concern about the cardiovascular side effect profile of sunitinib.4
One recent study showed 28% and 47% of patients on sunitinib for gastric stromal tumours, developing reduced left ventricular ejection fraction (LVEF) and hypertension, respectively, in association with sunitinib treatment. In addition ambulatory blood pressure monitoring suggests that most patients will experience significant increases in blood pressure while on sunitinib irrespective of their pre-morbid status, and that this rise in blood pressure may accelerate with subsequent cycles of treatment.5
Although both the theoretical risk of thrombosis and bleeding is well documented with anti-VEGF treatments, this is the first documented case of a thrombotic or any stroke possibly attributed to this treatment. Sunitinib has been associated with hypertensive microangiopathic reversible posterior leucoencephalopathy,6
but to our knowledge this is the first reported case of stroke possibly associated with its use. We classified the stroke as being of ‘undetermined aetiology’ using TOAST criteria; though embolic in nature by MRI infarct appearances, there did not appear to be a readily identifiable source on carotid and cardiac imaging or monitoring. The patient did have significant risk factors, however, including a history of smoking and hypertension and an underlying malignancy, itself a risk factor for thrombotic events. However we feel the recent literature, in conjunction with this case, highlights the need for continued cardiovascular vigilance and provision of appropriate advice and preventative treatments to high risk patients commencing anti-VEGF treatments
- Cancer is associated with an increased risk of stroke due to the disease itself, paraneoplastic phenomena, and possibly newer chemotherapeutic agents.
- Anti-vascular endothelial cell growth factor (anti-VEGF) receptor agents such as the tyrosine kinase inhibitor, sunitinib, are associated with sustained hypertension, left ventricular dysfunction, and may also be associated with occlusive microangiopathic disease that could result theoretically in either haemorrhagic or ischaemic stroke.
- This first probable association of acute ischaemic stroke with sunitinib therapy highlights the need for ongoing cardiovascular surveillance and appropriate preventative treatment in cancer patients on anti-VEGF treatments.