Cabozantinib-induced heart failure

Abstract

Introduction

Cabozantinib is a multikinase inhibitor agent used in the treatment of hepatocellular, renal, and thyroid cancers. The development of heart failure after cabozantinib initiation is an extremely rare side effect, with only four case reports published in the literature. We describe a case of cabozantinib-induced cardiac failure in a patient with thyroid cancer refractory to standard treatment.

Case report

Fifty-seven-year-old woman had no history of cardiovascular disease. Echocardiography prior to chemotherapy revealed normal cardiac function. However, she developed pretibial edema and shortness of breath after 2 months of cabozantinib treatment. Ejection fraction was found to be 30% in the echocardiography of the patient, and global hypokinesia was detected in cardiac functions.

Management and outcome

Cabozantinib treatment of the patient was discontinued. After discontinuation of treatment, the patient's cardiac functions did not return to normal. Heart failure due to cabozantinib treatment was thought to be permanent.

Discussion

There are only four cases on this subject in the literature. Although the use of cabozantinib rarely causes heart failure, this side effect can have extremely serious consequences. Even if it is a rare condition, cardiological evaluations should be performed before and after cabozantinib therapy because it can be reversible after discontinuation of the treatment.

Introduction

Differentiated thyroid cancer is the fifth most common cancer and radioactive iodine (RAI) is used as a standard treatment in metastatic setting. If progression develops, tyrosine kinase inhibitors are used in the treatment (sorafenib, lenvatinib, vandetanib, etc.). Cabozantinib is also a multikinase inhibitor agent used in the treatment of patients with metastatic thyroid cancer that progresses after RAI treatment. Studies have shown that cabozantinib contributes to survival in these patients.^1,2 Common side effects of cabozantinib include hypertension; endocrine and metabolic problems such as hyperglycemia, hyponatremia; and gastrointestinal problems such as abdominal pain and low appetite. The development of heart failure after cabozantinib initiation is an extremely rare side effect, with only four case reports published in the literature. We describe a case of cabozantinib-induced cardiac failure in a patient with thyroid cancer refractory to standard treatment. Informed consent was obtained from the patient and the patient's family for publication of the case report.

Case report

A 57-year-old female was admitted to the outpatient clinic with complaints of pretibial edema and shortness of breath. She had a history of thyroidectomy in 2010 and diagnosed with papillary thyroid cancer, received RAI treatment after the operation. In 2015, pulmonary multiple nodules, mediastinal lymphadenopathies and a mass in the posterior sternum were detected; biopsy from the nodule in the lung was found to be papillary thyroid carcinoma metastasis, and the patient was treated with RAI again. Subsequent basements she received lutetium, sorafenib, doxorubicin and reoperations for metastatic lesions and lymph nodes. After last visit, progresion occured and cabozantinib 60 mg once daily was started in June 2022. Echocardiography is performed before treatment and ejection fraction (EF) is detected as 60% in the echocardiography.

After 2 months of cabozantinib treatment, the patient was admitted to the outpatient clinic with complaints of swelling in the legs and shortness of breath. In the physical examination of the patient, rales were heard at the base of the lungs; neck venous distention and pretibial edema were observed. The patient's blood pressure was measured as 90/60 mmHg. The patient was referred to cardiology due to heart failure findings on physical examination. EF was found to be 30% in the echocardiography of the patient; global hypokinesia was detected in cardiac functions. Cabozantinib-related cardiotoxicity was primarily considered after excluding other causes of heart failure. Due to heart failure, the patient was started on oral treatment with furosemide and fluid restriction. Cabozantinib treatment of the patient was discontinued. Six months later, in December 2022, echocardiography showed that the patient's EF was still 30%. As the patient's bilateral pretibial edema persisted and shortness of breath was observed when she moved intensely, the oral furosemide treatment previously started by cardiology was revised and fluid restriction was continued. Cabozantinib was not planned to be restarted to the patient whose heart failure continued. The patient continued to be followed up without medication and PET CT scan in August 2023 showed progression in cervical and mediastinal lymph nodes, post-sternal mass, and skeletal lesions. As a result of the medical council attended by medical oncology and endocrinology departments, the patient was planned to receive an additional dose of RAI, which was administered in September 2023. Response evaluation tests after RAI treatment have not been performed yet. Naranjo Adverse Drug Reaction Probability Scale score was calculated as 7 in this case.

Discussion

Cabozantinib is a multikinase inhibitor used in cancers such as renal cell cancer, hepatocellular cancer, and thyroid cancer, showing anti-tumoral properties by inhibiting MET and VEGFR. Studies have shown that cabozantinib treatment in progressive thyroid cancer prolongs survival.^3,4 In our case, we started cabozantinib treatment in progressive thyroid cancer.

During treatment with multikinase inhibitors, patients sometimes develop cardiac side effects. A retrospective pharmacovigilance study investigated the cardiac side effects that developed in patients treated with anti-VEGFR tyrosine kinase inhibitors. ⁵ The most common cardiac adverse events in the patients in this study were hypertension (11% of patients) and bleeding (7% of patients). Cardiac side effects observed less frequently were heart failure (1.7% of patients), pericardial diseases (0.1% of patients), and aortic dissection (0.1% of patients). In our case, heart failure developed in a patient treated with anti-VEGFR tyrosine kinase inhibitor. The patient's blood pressure was normal; fluid overload or heart failure due to hypertension was not considered.

Heart failure is an extremely rare adverse event in cabozantinib treatment. There are only four cases on this subject in the literature. In a case report published by Ishiguchi et al., the patient developed acute heart failure after cabozantinib use. ⁶ In a case report by Buttar et al., it was observed that severe cardiac dysfunction developed after cabozantinib treatment. ⁷ In a case report by Verran et al., the patient develops heart failure after cabozantinib treatment and despite maximal medical therapy for the patient, the heart failure became irreversible and contributed to his death. ⁸ In these three reports, heart failure slightly improved after discontinuation of cabozantinib treatment; however, it was stated that it did not return to normal completely. In a case report published by Alhussein et al., it was observed that the patient developed heart failure due to cabozantinib, and cardiac functions returned to normal after treatment was discontinued. ⁹ In our case, heart failure developed due to cabozantinib treatment. In the subsequent evaluation of the patient, echocardiography showed that the patient's EF was still 30% and cabozantinib-induced heart failure was thought to be permanent.

Conclusions

Cabozantinib is one of the alternative treatments in the advanced treatment of differentiated thyroid cancers. Although the use of cabozantinib rarely causes heart failure, this side effect can have extremely serious consequences. Cardiological evaluations should be performed before and after cabozantinib therapy. Cabozantinib therapy should be used more carefully in patients with cardiac risk factors. More comprehensive studies are needed to understand the cardiotoxic side effects of cabozantinib.

Supplemental Material

sj-docx-1-opp-10.1177_10781552231203703 - Supplemental material for Cabozantinib-induced heart failure

Supplemental material, sj-docx-1-opp-10.1177_10781552231203703 for Cabozantinib-induced heart failure by Serhat Sekmek, Dogan Bayram, Gokhan Ucar, Burak Civelek, Fahriye Tugba Kos and Dogan Uncu in Journal of Oncology Pharmacy Practice