Regorafenib-Induced Hyperammonemic Encephalopathy in Metastatic Colon Cancer

Regorafenib, a multi-targeted tyrosine kinase inhibitor (TKI), is used in metastatic colorectal cancer (mCRC) and gastrointestinal stromal tumors (GIST) for salvageline therapy. From clinical trials, the most commonly reported adverse events of regorafenib are hand-foot skin reactions, fatigue, diarrhea and hypertension. We report two cases of hyperammonemic encephalopathy induced by regorafenib in patients with mCRC. Hyperammonemic encephalopathy is a life-threatening complication in patients with severe liver cirrhosis, and is often observed in liver dysfunction/failure cases. Cases of hyperammonemic encephalopathy have been reported with various multi-targeted TKIs. The underlying mechanism of encephalopathy remains unclear, but in light of similar presentations, it can be reasonably suspected to be a result of a class effect of these TKIs. We suggest checking ammonia levels in patients on regorafenib presenting with altered consciousness, even if they have normal liver function. Discontinuation of regorafenib, as well as ammonia-lowering therapy, is essential to the management of this adverse effect, and recommencement of regorafenib should be discouraged.