Management of Cardiac Adverse Events Occurring with Sunitinib Treatment

Case Report

Sunitinib malate is an oral, multitargeted receptor tyrosine kinase inhibitor, approved multinationally for the first-line and second-line treatment of advanced and/or metastatic renal cell carcinoma (mRCC). Sunitinib has shown substantial efficacy in the first-line treatment of mRCC (1) and is now considered the reference standard of care in this setting (2). In a randomised, phase III trial in patients with previously untreated mRCC, sunitinib was associated with median progression-free survival more than double that observed with interferon-alfa (IFN-α) (11.0 months vs. 5.1 months, respectively; p<0.000001) (3). Sunitinib was also superior to IFN-α with respect to objective response rate (47% vs. 12%, respectively; p<0.000001) (3). In addition, sunitinib was associated with median overall survival (OS) of more than 2 years in this study (26.4 months vs. 21.8 months for IFN-α; p=0.051) (3). Patients were permitted to cross over from IFN-α to sunitinib in the study. To account for this, an analysis was performed on patients who received only their on-study treatments, where median OS was found to be 28.1 months for sunitinib compared with 14.1 months for IFN-α (p=0.0033) (3).

Cardiovascular adverse events (AEs) have been observed with sunitinib treatment. In the phase III trial in patients with mRCC, 24% of patients treated with sunitinib reported hypertension of any grade (1). The incidence of grade 3 decline in left ventricular ejection fraction (LVEF) was similar in both the sunitinib and IFN-α groups (2% vs. 1%) in this trial (1). The presenting study group recently reported electrocardiogram (ECG) changes in 40.5% of patients treated with either sunitinib or the multikinase inhibitor, sorafenib (4). Here a case in which cardiac AEs experienced during sunitinib treatment were successfully managed is presented.

Patient background. A 49-year-old male patient underwent nephrectomy in June 2005 following diagnosis of clear-cell RCC with venous invasion but no distant metastases (pT3b, pNx, M0). In March 2006, the patient was diagnosed with mRCC with lung and bone metastases. The patient presented with an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 3, increased corrected calcium (1.55 mmol/L [normal range: 1.16-1.32 mmol/L]), elevated lactate dehydrogenase (539 u/L [normal: <248 u/L]) and anaemia. He was thus considered to be at poor prognostic risk according to the Memorial Sloan-Kettering Cancer Center (MSKCC) classification (5). In addition, the patient was wheelchair-bound due to weakness and pain.

Treatment. Sunitinib was initiated at the end of March 2006 using the standard dose of 50 mg/day on Schedule 4/2 (4 weeks on treatment followed by 2 weeks off treatment) following diagnosis of lung and bone metastases. Minor toxicities (≤ grade 2) emerging upon sunitinib treatment included slight increases in blood pressure, anaemia, neutropenia and thrombocytopenia. Following two 6-week cycles of sunitinib, the patient was admitted to hospital for severe dyspnoea. His blood pressure had reduced to 90/60 mmHg and tests revealed oedema, in addition to pleural and pericardial effusions (Table I). Reduced ejection fraction (EF) of 26%, low-voltage ECG and regional contraction disturbances were observed. Cardiac troponin was detected at a level of 0.04 ng/mL. Coronary angiography revealed no significant obstructive coronary artery disease.

The patient was prescribed an angiotensin-converting enzyme (ACE) inhibitor (lisinopril 5 mg/day initiated and increased up to 30 mg/day), diuretics (spironolactone 100 mg/day and furosemide 40 mg/day) and a β-blocker (carvedilol 6.25 mg initiated twice daily and increased up to 25 mg twice daily). Sunitinib treatment was also interrupted. After 10-days of receiving cardiovascular co-medication, complete cardiac compensation occurred, including disappearance of pericardial/pleural effusions and oedema; blood pressure was normalised. Sunitinib was resumed at a reduced dose of 25 mg/day and the patient was discharged after 3 weeks in the hospital. Sunitinib dosage was subsequently increased to 37.5 mg/day. The patient remains on ACE inhibitors and β-blockers; diuretics were stopped after 3 months of treatment.

The patient survived without mRCC disease progression for 25.0 months, ending in April 2008. The patient's OS is >31 months since the start of sunitinib treatment. These findings are significant considering the patient was initially classified at poor risk according to MSKCC criteria, with an expected PFS of only 2.5 months and OS of just 5 months according to historical data (5). Throughout sunitinib treatment, there have been continuous improvements in the patient's quality of life, determined using clinical assessments. In addition, the patient has experienced no pain and was able to walk and participate in moderate exercise programmes. As of November 2007, disappearance of lung metastases and minor remission of spinal metastases were observed and confirmed by a computed tomography scan. The patient's performance status also improved to an ECOG PS of 1.