Case Presentation: The patient is 67-year-old man with prior metastatic renal cell carcinoma (status post right nephrectomy), on long term pazopanib therapy, who presented with dyspnea and pleurisy. He was found to be in hypoxemic respiratory distress out of proportion to the mild pulmonary vascular congestion seen on his initial chest x-ray (CXR). He improved on non-invasive positive pressure ventilation, transitioned to nasal canula, and was started on anticoagulation and antibiotics for a suspected pulmonary embolism (PE) and presumed pneumonia. However, he soon decompensated with increasing oxygen requirements and new lower extremity swelling. Imaging studies were negative for a PE. Repeat CXR revealed a new large left sided pleural effusion and diffuse pulmonary vascular infiltrates. An echocardiogram revealed a left ventricular ejection fraction of 35% (previously normal) in the setting of a negative acute coronary syndrome workup. After discussing with consultant teams, the patient was trialed on prednisone 60mg daily for possible pazopanib induced pneumonitis and heart failure, with drastic improvement in his pulmonary infiltrates and hypoxemia. His pleural effusion also resolved with diuretics. Pazopanib was discontinued, and the patient was completely weaned off oxygen by discharge. Follow up CXR revealed resolution of his pulmonary infiltrates.
Discussion: Angiogenesis inhibitors are increasingly common medications with specific adverse effects that need to be noted. These medications all act via inhibition of the vascular endothelial growth factor (VEGF), which regulates development of new vascular endothelium. Angiogenesis is considered the rate-limiting step for tumor progression. Subclasses include Anti-VEGF antibodies (bevacizumab), decoy receptors (afilbercept), and non-specific tyrosine kinase inhibitors (TKI’s) like pazopanib, sorafenib, or sunitinib. These TKI’s not only target VEGF but also receptors of platelet-derived growth factor and fibroblast growth factor, which increases both scope of efficacy and the scope of toxicity. All antiangiogenic medications have risk for cardiovascular toxicities. Hypertension is the most common, and blood pressures should be monitored routinely. Systolic dysfunction has also been documented: a systematic meta-analysis has shown that patients on antiangiogenic TKI’s are 2.5 times more likely to develop heart failure than the ordinary population. Certain TKI’s have been implicated in ischemic events as well. In most studies, discontinuation led to improvement in cardiac function. Other risks include proteinuria, bleeding, hypothyroidism, and hepatotoxicity. Although pneumonitis is not a well-established toxicity, there are few case reports showing serious or fatal drug-induced interstitial lung disease or pneumonitis in patients taking pazopanib. We believe our patient experienced a similar pneumonitis that, in the setting of new heart failure, put him at risk for respiratory failure. This was evidenced by his response to steroids and sustained improvement after discontinuation of pazopanib.
Conclusions: Anti-angiogenic TKI’s have side effects that can lead to serious toxicities and morbidities at any point of their administration. Recognition and discontinuation of the drug is essential. The hospitalist physician must be aware of such side effects and keep these toxicities in the differential, especially as new classes of medications develop and become routinely encountered in everyday practice.