Introduction
As an oral, multi-target tyrosine kinase inhibitor, sunitinib has a direct anti-tumor effect as well as an effect against angiogenic activity, acting via several types of tyrosine kinase receptors (1). According to the European Medicines Agency, it is registered for the treatment of gastrointestinal stromal tumors when surgical treatment is not possible and imatinib therapy has already been administered, as well as in metastatic kidney cell carcinoma and advanced neuroendocrine pancreatic cancer (2). Despite having many positive effects, sunitinib also causes unwanted effects in some patients. These include hemorrhagic events, digestive disorders, skin disorders, kidney function disorders, pancreatic disorders, hypertension, arterial and venous thromboembolic events, and even aneurisms and arterial disections (3,4). In addition to these unwanted events, certain forms of heart function disorders have also been reported. The most common are myocardial ischemia and reduction in left ventricular ejection fraction, with the less common ones including congestive heart failure, myocardial infarction, pericardial effusion, and QT interval prolongation, and Torsades de Pointes arrhythmia being a rare effect.
Case report
In May 2022, a 73-year-old man was hospitalized at the Clinic for Heart and Vascular Diseases with a clinical picture of acute myocardial infarction with ST-segment elevation. He initially presented by ambulance vehicle to the Integrated Emergency Hospital Admission (IEHP) department for dull aches in the chest that had manifested on the day of admission at approximately 8.30. Arrival at the IEHP was recorded as late as seven hours after appearance of the symptoms. The pain was dull, strongest in the middle of the chest with propagation to the right arm, and was accompanied with cold sweats.
Earlier, the patient had been treated twice for primary prostate and kidney tumors. A radical prostatectomy had been performed in 2015, and normal PSA markers were observed during follow-up. In 2021, a neoplasm was observed in the right kidney, with metastases in the left adrenal gland. Radical right-side nephrectomy and right-side adrenalectomy were performed in July, 2021. Clear cell carcinoma was subsequently histologically confirmed. In October, three months after the surgical treatment, biological therapy with sunitinib 50 mg was started, using a schema of 4 weeks of drug intake followed by a 2-week pause. The dose was reduced to 37.5 mg in April 2022. The patient was without subjective complaints during the whole treatment period, and laboratory monitoring observed elevated creatinine levels of 120 to 150 μmol/L. The last oncological examination had been performed at the end of April, a week before the onset of acute coronary syndrome (ACS). Of the potential comorbidities that could have contributed to the development of ACS, the patient suffered from obesity, whereas arterial hypertension, diabetes, hypercholesterolemia, and smoking had not been observed.
The emergency medical team administered prehospital 300 mg aspirin and 180 mg of ticagrelor. Immediately upon presentation to the IEHP, examination showed normal vital parameters and unremarkable clinical heart and lungs status. Based on the recommended treatment protocol, a 12-lead electrocardiogram was immediately performed to verify sinus rhythm, which was found to have a frequency of approximately 50/min with significant ST-segment elevation in the inferior, posterior, and lateral leads (Figure 1). Laboratory samples were collected, a PCR test for SARS-COV-2 was performed, and the patient was rapidly prepared for invasive cardiological procedure. Emergency coronarography showed unremarkable morphology of the left main continuing into a tortuous left anterior descending artery and circumflex artery, also of unremarkable morphology. The dominant right coronary artery was occluded in the proximal segment (Figure 2), and primary percutaneous coronary intervention was continued. The acute occlusion was successfully passed with the guide wire, and predilatation was performed with a balloon catheter. Coronary angiography showed outflow thrombi up to beyond the crux, and an aspiration catheter could not be used due the tortuosity of the middle segment. Two drug-eluting stents were placed in the abovementioned segments, followed by aspiration thrombectomy and mechanical thrombectomy that was successful in extracting multiple blood clots, but the distal flow was still TIMI 0/1 despite the treatment. Further dilatation of all segments with a balloon catheter was performed, and TIMI 1/2 was achieved despite numerous blood clots (Figure 3). After the procedure, 24-hour tirofiban infusion was prescribed. Elective recoronarography was planned to reevaluate the condition.
After the intervention, the patient was placed in the intensive cardiological treatment ward, and the laboratory findings for the previously collected samples became available. The most notable results were high-sensitivity troponin T values at 365 ng/L (reference value <14) and creatinine 137 μmol/L. The patient developed hemiplegia on the same day. An emergency thrombectomy protocol was initiated, but brain CT, CT brain perfusion, and CT angiography of cerebral and carotid arteries did not find any pathomorphological substrate for the patient’s issues. Thus, no neurointerventional treatment or systemic thrombolysis were indicated. Spontaneous recovery of neurological status occurred on the next day, but laboratory findings showed a significant increase in high-sensitivity troponin T to over 18.000 ng/L as well as an increase in creatinine to 167 μmol/L. On the third day, the patient became febrile, with a temperature of up to 38 °C; blood and urine samples were taken, and ceftriaxone was introduced based on previous experience. Laboratory results showed deterioration of renal function parameters and an increase in creatinine to 305 μmol/L, CRP-to 165 mg/L, and procalcitonine to 1.19 μg/L. Due to reduced diuresis and suspected post-contrast nephropathy, parenteral and peroral liquid intake was increased, and continuous furosemide was introduced. Hemodynamic collapse occurred on the fourth day of the patient’s hospital stay, and inotropic and vasoactive support using dobutamine and noradrenaline was initiated. Despite the previously prescribed treatment, creatinine increased to 528 μmol/L, and venovenous hemodiafiltration was initiated on the nephrologist’s recommendation. Ultrasound showed reduced biventricular contractility with hemodynamically insignificant pericardial effusion in front of the right ventricle. The patient’s condition deteriorated despite all the treatment measures, with the development of irreversible hemodynamic collapse leading to a fatal outcome on the fifth day of hospitalization.
Discussion
Numerous side-effects of sunitinib have been listed in the Introduction section, with an emphasis on those that are associated with the cardiovascular (CV) system. This has become the topic of numerous studies. Schmidinger et al. examined the cardiotoxicity of sunitinib and sorafenib in patients with metastatic kidney cancer (5). At the beginning of their paper, they also state that cardiotoxic effects develop in approximately 10% of patients undergoing treatment with tyrosine kinase inhibitors. Consequently, the issue of the need for higher-quality CV monitoring must be addressed in order to detect signs of myocardial damage in the early phase. The goal of the study was to monitor the clinical, biochemical, and echocardiographic signs of myocardial damage, and it was conducted on 86 patients. A CV event was defined as increase in necrosis markers, symptomatic arrhythmia, newly-developed ventricular dysfunction, and ACS. Out of the total number of patients, almost 34% experienced some CV event. A third of these patients underwent coronary angiography, but no abnormalities were detected in any of them. In their conclusion, the authors state that heart damage caused by tyrosine kinase inhibitors is greatly underestimated. Given that the mechanism of heart damage is not known, regular echocardiographic and biochemical evaluation is clearly a necessity.
Catino et al. conducted a multicentric prospective study that examined the influence of sunitinib on the CV system (6). The study included a total of 84 patients who suffered from metastatic kidney cancer. The results showed an increase in systolic pressure by an average of 9.5 mmHg and an increase in diastolic pressure of 7.2 mmHg after 3.5 weeks of sunitinib application. Additionally, the authors concluded that arterial stiffness and their peripheral resistance had increased, and their elasticity had decreased.
Abbondanza Pantaleo et al. published a case report in which they described the development of coronary artery stenosis in a patient treated with sorafenib (7). In the introductory part of the paper, they state there are several reported cases of coronary heart disease associated with sorafenib therapy, i.e. with tyrosine kinase inhibitors. Arterial vasospasm was the underlying cause in these cases, without stenosis verified by angiography. This case report described a 58-year-old patient without modifiable CV risk factors. Due to the discovery of a kidney tumor with metastases, the patient was initially treated surgically, followed by sorafenib therapy. Before tyrosine kinase inhibitors were introduced, a heart ultrasound and coronary angiography were performed, which were unremarkable. After approximately two years of treatment, the patient complained of lack of tolerance to exertion and occasional chest pains. Coronarography was performed shortly thereafter, which showed a subocclusive lesion of the left main trunk and the middle part of the circumflex artery. Consequently, the patient underwent cardiac surgery – a triple coronary artery bypass was performed. It is important to note that the patient had been undergoing regular follow-up during the entire treatment period.
A meta-analysis by Ranpure et al. examined studies published on this topic and evaluated the risk of myocardial ischemia and thromboembolic events in patients on angiogenesis inhibitors, in this case bevacizumab (8). A total of 2322 patients were included, and the results showed that the total incidence of severe heart ischemia was 1.5%, and the relative risk in comparison with the control group was 2.14, which indicates that the application of bevacizumab significantly increases the risk of heart ischemia, namely by 114%.
Conclusion
Tyrosine kinase inhibitors certainly have a significant role in the treatment of specific types of tumors, but this does not mean that their potential negative effects should be neglected. Literature analysis regarding the cardiotoxic side-effects of these medications leads to the conclusion that these side-effects are common: according to some studies, they develop in approximately 10% of patients. This issue elicits additional attention due to the fact that the mechanism of cardiotoxicity itself is not known. The development of ACS described in this case report cannot be ascribed to the effects of sunitinib with certainty, but the analysis of a similar case described above that was reported by Italian authors shows that the potential association cannot be ignored, especially since the patients were monitored and did not have significant CV comorbidities. Due to all of the above, it is important to emphasize the irreplaceable role of performing high-quality CV monitoring during the application of this therapy. This could allow timely detection of unwanted CV events, making adjustments in oncological treatment, and thus avoid stopping treatment for the malignant disease.