How should sorafenib (sorafenib) be used in patients with hepatic encephalopathy?

Sorafenib and Hepatic Encephalopathy

Direct Recommendation

Sorafenib should be used with extreme caution in patients with any degree of hepatic encephalopathy, and is generally contraindicated in those with overt encephalopathy, as it can precipitate or worsen this condition even in patients with preserved liver function. 1

Evidence-Based Approach

Risk Assessment Before Initiating Sorafenib

Sorafenib is only recommended for patients with Child-Pugh class A liver function as a category 1 recommendation. 1 For Child-Pugh class B7 patients, it carries a category 2A recommendation with extreme caution required. 1

• Patients with Child-Pugh class B liver function experience significantly higher rates of encephalopathy (along with hyperbilirubinemia and ascites) compared to Child-Pugh class A patients, though it remains difficult to separate drug toxicity from underlying liver dysfunction. 1

• The 2022 Korean guidelines report that Child-Pugh B8-9 patients experienced serious adverse events in 69% and 67% of cases respectively, compared to 54% in B7 patients and 36% in Child-Pugh A patients. 1

• Median overall survival decreases dramatically with worsening liver function: 13.6 months for Child-Pugh A, 6.2 months for B7, 4.8 months for B8, and 3.7 months for B9. 1

Clinical Evidence of Sorafenib-Induced Encephalopathy

Case reports and clinical series demonstrate that sorafenib can directly precipitate hepatic encephalopathy, which resolves within 24 hours of drug discontinuation and recurs upon rechallenge. 2, 3

• In one case series, 7 out of 10 patients with cognitive impairment during sorafenib treatment had overt hepatic encephalopathy, and 2 had drug-related toxic-metabolic encephalopathy that was unresponsive to conventional HE treatment but fully reversible with drug discontinuation. 3

• The mechanism appears to involve sorafenib's potential direct neuronal action serving as a trigger for metabolic encephalopathy in cirrhotic patients, separate from traditional HE precipitants. 3

Management Algorithm

If a patient develops hepatic encephalopathy while on sorafenib:

1. Immediately discontinue sorafenib - neurological symptoms typically resolve within 24 hours of withdrawal. 2, 3

2. Measure venous ammonia levels - elevated ammonia supports the diagnosis but sorafenib-induced encephalopathy can occur with normal ammonia. 2

3. Rule out other precipitants - perform routine investigations including brain imaging, exclude infection, gastrointestinal bleeding, electrolyte disturbances, and constipation. 2, 3

4. Initiate standard HE treatment (lactulose, rifaximin) but recognize that sorafenib-induced toxic-metabolic encephalopathy may not respond to these interventions. 3, 4

5. Do not rechallenge with sorafenib - encephalopathy recurs upon drug reintroduction, even at reduced doses. 2, 3

Contraindications and Special Populations

The 2022 AGA guidelines suggest against routine use of sorafenib in patients with poor liver function (Child-Pugh C). 1

• Patients with elevated bilirubin levels require extreme caution due to association with possible hepatic toxicity and higher encephalopathy risk. 1

• Meticulous follow-up is mandatory for Child-Pugh B patients, as liver-related adverse events occur frequently. 1

• Child-Pugh B8/9 patients require careful selection and close monitoring, as only limited safety data exist for this population. 1

Alternative First-Line Options

For patients at high risk of encephalopathy or with Child-Pugh B liver function, consider alternative systemic therapies:

• Lenvatinib is only recommended for Child-Pugh A patients and is not an option for those with impaired liver function. 5

• Atezolizumab plus bevacizumab has become a preferred first-line option but also requires preserved liver function. 1

Critical Pitfalls to Avoid

• Do not assume encephalopathy in a cirrhotic patient on sorafenib is solely due to liver disease progression - sorafenib itself can be the precipitant. 2, 3

• Do not attempt dose reduction and continuation - case reports show recurrence even at lower doses. 2

• Do not rely solely on conventional HE treatment - sorafenib-induced toxic-metabolic encephalopathy may require drug discontinuation for resolution. 3

• Do not use sorafenib in patients who already have any grade of hepatic encephalopathy - the risk of worsening is substantial. 1