pazopanib and Heart-Failure

Pazopanib, an oral multi-targeted tyrosine kinase inhibitor, is associated with improved outcomes in patients with unresectable or metastatic soft tissue sarcoma. Pazopanib may cause cardiotoxicity such as heart failure.. A 50-year-old female patient with no cardiovascular risk factors other than the previous treatment with adriamycin had a baseline left ventricular ejection fraction of 60%. She was receiving pazopanib 800 mg once daily for advanced leiomyosarcoma of the presacral area. On the 60th day of treatment, she presented with fatigue, palpitation, and exertional dyspnea for several days. Echocardiography was performed, and left ventricular ejection fraction was measured as 25%. Pazopanib-induced heart failure was considered and all other possible preliminary diagnoses were excluded.. Pazopanib was stopped immediately. Bisoprolol fumarate 5 mg orally once daily, spironolactone 100 mg orally once daily, furosemide 40 mg orally once daily, and ramipril 2.5 mg orally once daily were started. The patient's symptoms partially improved. Second echocardiography was performed after 15 days, and left ventricular ejection fraction was measured as 35%. But, despite pazopanib was not resumed and cardiac support treatment was administered, she died four weeks after discontinuation of pazopanib due to heart failure.. Pazopanib-induced heart failure may be fatal. Physicians and patients should be aware of the cardiotoxicity risk when managing the use of pazopanib in soft tissue sarcoma.

Topics: Doxorubicin; Dyspnea; Female; Heart Failure; Humans; Indazoles; Middle Aged; Protein Kinase Inhibitors; Pyrimidines; Sarcoma; Stroke Volume; Sulfonamides; Ventricular Function, Left

Soft-tissue sarcomas are rare tumours of mesenchymal origin. Patients with metastatic disease have a median survival of about 10 months. Doxorubicin, an anthracycline, is often used to reduce tumour volume, but it does not prolong overall survival. Pazopanib, a multiple tyrosine kinase inhibitor already marketed for kidney cancer, is now licensed for the treatment of certain metastatic soft-tissue sarcomas when chemotherapy fails or when the disease progresses despite adjuvant or neoadjuvant therapy. Clinical evaluation of pazopanib in this setting is based on a double-blind, randomised, placebo-controlled trial in 369 patients whose tumours had progressed despite at least one line of chemotherapy, based on an anthracycline. In this trial, pazopanib did not provide a statistically significant increase in overall survival. The median survival time was about 12 months. A statistically significant increase in median progression-free survival was observed (4.6 versus 1.6 months, an increase of 3 months), based mainly on radiological criteria. Pazopanib did not improve quality of life. The adverse effect profile includes cardiovascular, gastrointestinal and hepatic disorders, and palmoplantar erythrodysaesthesia. Serious adverse effects are frequent. Other life-threatening adverse effects observed in patients with soft-tissue sarcoma include pneumothorax (especially in case of pulmonary metastasis), heart failure, venous thrombosis, pulmonary embolism and hypothyroidism. In practice, given its lack of any proven impact on overall survival and its excessive toxicity, the use of pazopanib is not justified. It is better to focus on appropriate symptomatic care in order to preserve these patients' quality of life.

Topics: Angiogenesis Inhibitors; Double-Blind Method; Heart Failure; Humans; Indazoles; Liver; Pneumothorax; Protein Kinase Inhibitors; Pyrimidines; Quality of Life; Sarcoma; Sulfonamides

Pharmacovigilance signals of heart failure (HF) following exposure to protein kinase inhibitors (PKIs) have been detected in recent years. Our aim was to identify the PKIs most frequently associated with the development of HF.. Using the French National Healthcare Database, all patients newly exposed to a PKI between January 2011 and June 2014 were followed up for 18 months. Specific hospitalization diagnosis and long-term HF-related disease codes were used to identify HF patients. HF incidence rate ratios (IRRs) were measured and adjusted hazard ratios (aHRs) were estimated using a Cox model. Sensitivity analyses were performed to limit the potential indication and competitive risk bias.. Thirteen PKIs were studied. Among the 49 714 new PKI users registered during the study period, the mean IRR of HF was 3.38 per 100 person-years, with a median time to onset of 155 days. We found a significant increase in the incidence of HF for six medicinal products: pazopanib (aHR = 2.42, 95% confidence interval [CI] 1.67-3.52), dasatinib (aHR = 2.22, 95% CI 1.42-3.44), ruxolitinib (aHR = 2.11, 95% CI 1.69-2.64), crizotinib (aHR = 1.71, 95% CI 1.07-2.72), everolimus (aHR = 1.45, 95% CI 1.26-1.67) and vemurafenib (aHR = 1.37, 95% CI 1.01-1.86). Sensitivity analyses were consistent with our primary analysis.. The current study provides knowledge on HF following exposure to a PKI. Additional studies could confirm these results for dasatinib, everolimus, pazopanib and ruxolitinib, and particularly for the two medicinal products with results slightly above the significance threshold, namely, crizotinib and vemurafenib, in our sensitivity analyses.

Topics: Crizotinib; Dasatinib; Everolimus; Heart Failure; Humans; Incidence; Protein Kinase Inhibitors; Vemurafenib

We sought to examine cardiovascular toxicities associated with tyrosine kinase inhibitors in pediatrics. We examined 1624 pediatric adverse events with imatinib, dasatinib, sorafenib, pazopanib, crizotinib, and ruxolitinib reported to the Food and Drug Administration between January 1, 2015, and August 14, 2020. There were 102 cardiovascular event reports. Hypertension was the most commonly reported cardiovascular event and was most frequently associated with sorafenib and pazopanib. The presence of infection increased the reporting odds of cardiovascular events overall and specifically cardiac arrest, heart failure, and hypertension. These data provide early insight into cardiovascular toxicities with tyrosine kinase inhibitor use in pediatrics.

Topics: Antineoplastic Agents; Child; Heart Failure; Humans; Hypertension; Protein Kinase Inhibitors; Sorafenib; Tyrosine Kinase Inhibitors; United States; United States Food and Drug Administration

Tyrosine kinase inhibitors (TKIs) can cause cardiotoxicity, and some suggest routine monitoring of cardiac function during TKI use. We describe two cases of TKI-induced heart failure (HF) that suggest the utility of monitoring with laboratory tests is questionable. One patient developed HF 5 days after starting pazopanib. The other developed HF while receiving 25 mg per day sunitinib, and had previously received a higher dose (50 mg per day) with no symptoms of cardiotoxicy. In addition, she later received 5 cycles of sunitinib (25 mg per day) without developing an abnormal left ventricular ejection fraction (LVEF) value by echocardiography or cardiac symptoms. Although the LVEF is commonly performed to monitor TKI cardiotoxicity, evidence for its predictive utility is limited. These cases raise questions regarding the practical utility of sequential measurement of LVEF in adults treated with TKIs. We suggest a simple daily activity such as stair climbing to monitor exercise tolerance.

Topics: Aged; Carcinoma, Renal Cell; Female; Heart Failure; Humans; Indazoles; Kidney Neoplasms; Leiomyosarcoma; Middle Aged; Prognosis; Protein Kinase Inhibitors; Pyrimidines; Sulfonamides; Sunitinib

A 70-year-old man with history of stage IV renal cell carcinoma, chronic atrial fibrillation on warfarin, coronary artery disease status post-percutaneous coronary intervention resulting in an ischaemic cardiomyopathy with left ventricular ejection fraction of 40%-45%, presented with shortness of breath 10 days after starting pazopanib. Within the first week of starting pazopanib, the patient developed fatigue and progressive dyspnoea on exertion. His symptoms quickly worsened and he had compromised mental status. He was transferred to the intensive care unit (ICU) and intubated due to continued respiratory distress. He was found to be in cardiogenic shock and was started on inotropic support with dobutamine and norepinephrine. With maximum support, the patient was slowly weaned off vasopressors and was successfully extubated on ICU day 9. His hospital stay lasted 29 days with management of multiple medical complications, and he was eventually discharged to a rehabilitation facility.

Topics: Aged; Antineoplastic Agents; Carcinoma, Renal Cell; Heart Failure; Humans; Indazoles; Kidney Neoplasms; Male; Pyrimidines; Sulfonamides

Topics: Carcinoma, Renal Cell; Drug Administration Schedule; Heart Failure; Humans; Indazoles; Kidney Neoplasms; Male; Middle Aged; Paraneoplastic Syndromes; Pyrimidines; Stroke Volume; Sulfonamides; Treatment Outcome

Topics: Adult; Chemical and Drug Induced Liver Injury; Fatal Outcome; Female; Heart Failure; Humans; Indazoles; Pyrimidines; Sarcoma; Soft Tissue Neoplasms; Sulfonamides

Topics: Aged; Angiogenesis Inhibitors; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Carcinoma, Renal Cell; Heart Failure; Humans; Indazoles; Kidney Neoplasms; Male; Pyrimidines; Sulfonamides

Tyrosine kinase inhibitors, represented by sunitinib, sorafenib, axitinib and pazopanib, are emerging molecules harbouring antitumoural efficacy in multiple neoplasia. We report the case of a 51-year-old woman with right thoracic sarcoma who developed fatal heart failure on pazopanib. The patient had no cardiovascular risk factor, except previous exposure to anthracycline, and her cardiac function was normally controlled before initiating the pazopanib. Despite a rapid tumour response, fatigue rapidly appeared, requiring treatment interruption 2 weeks after pazopanib introduction. After clinical improvement, the pazopanib was reintroduced at reduced dose; however, a few days later, our patient was admitted for worsening dyspnoea and fatigue. Pulmonary embolism was excluded as was pleuropericardial effusion. Brain natriuretic peptide was the only laboratory abnormality, and echocardiography revealed acute and severe heart failure. The patient died despite pazopanib arrest and inotropic support.

Topics: Antineoplastic Agents; Dyspnea; Fatal Outcome; Fatigue; Female; Heart Failure; Humans; Indazoles; Middle Aged; Pyrimidines; Sarcoma, Synovial; Sulfonamides; Thoracic Neoplasms