To Prevent Hepatotoxicity, Monitor Liver Function During Cancer Treatment

Liver Function Tests

Elevated liver enzymes can reflect damage to the liver, biliary obstruction, or impaired synthetic function. Alanine aminotransferase (ALT), aspartate aminotransferase, alkaline phosphatase, and bilirubin are biochemical markers of liver injury. Albumin, bilirubin, and prothrombin time are markers of hepatocellular function. ALT is present primarily in the liver and serves as a more specific marker of hepatocellular injury (https://www.uptodate.com/contents/approach-to-the-patient-with-abnormal-liver-biochemical-and-function-tests). Serum bilirubin level is the most frequently used parameter to adjust chemotherapy dosing, but it may be an oversimplified approach (https://www.cancernetwork.com/oncology-journal/chemotherapy-dosing-setting-liver-dysfunction). 

The National Cancer Institute identified grading based on liver function tests (https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_8.5x11.pdf) in the Common Terminology Criteria for Adverse Events (see sidebar) to provide for consistency and guidance on appropriate interventions. For example, dose reduction or holding treatment may be necessary for agents that depend on liver function for metabolism (http://doi.org/10.14218/JCTH.2014.00011). 

Hepatotoxic Cancer Drugs

Although all patients with hepatic dysfunction should be treated cautiously, use of certain agents provokes greater concern than other agents. Continuous-infusion fluorouracil, capecitabine, cyclophosphamide, topotecan, and oxaliplatin appear to be relatively well tolerated; however, taxanes, vinca alkaloids, irinotecan, and anthracyclines may cause unacceptable toxicity in patients with poor hepatic function (https://www.cancernetwork.com/oncology-journal/chemotherapy-dosing-setting-liver-dysfunction). 

Immunotherapy can cause hepatotoxicity in about 5%–10% of patients (https://doi.org/10.21037/atm.2016.07.10) as soon as 6–12 weeks after beginning immunotherapy. Hepatitis is usually asymptomatic and detected on blood monitoring. If it develops, disease-related concerns, concomitant drug administration, and infectious causes should be ruled out and imaging and liver biopsy should be considered. If immune-mediated hepatitis is suspected, consider using steroids, holding the drug, and admitting patients to the hospital for daily monitoring of liver function tests. 

According to the National Comprehensive Cancer Network (NCCN) (https://www.nccn.org/professionals/physician_gls/pdf/immunotherapy.pdf), for grade 1 transaminitis without elevation of bilirubin, immunotherapy can be continued with more frequent lab value monitoring. For grade 2 transaminitis, NCCN recommended holding the drug, repeating liver function tests every three to five days, and considering prednisone 0.5–1 mg/kg per day. If a severe or grade 3 transaminitis develops during immunotherapy, permanently discontinue the drug, initiate prednisone 1–2 mg/kg per day, and consider inpatient care and hepatology consult. 

Providers need to exercise knowledge and caution when deciding on necessary interventions. For dosing guidelines, refer to each medication’s package insert. 

Common Terminology Criteria for Adverse Events: Liver Function Testing 

Test	Grade 1	Grade 2	Grade 3	Grade 4
Alanine aminotransferase	> ULN–3.0 x ULN if baseline was normal; 1.5 - 3.0 x baseline if baseline was abnormal	> 3.0–5.0 x ULN if baseline was normal; > 3.0–5.0 x baseline if baseline was abnormal	> 5.0–20.0 x ULN if baseline was normal; > 5.0–20.0 x baseline if baseline was abnormal	> 20.0 x ULN if baseline was normal; > 20.0 x baseline if baseline was abnormal
Alkaline phosphatase	> ULN–2.5 x ULN if baseline was normal; 2.0–2.5 x baseline if baseline was abnormal	> 2.5–5.0 x ULN if baseline was normal; > 2.5–5.0 x baseline if baseline was abnormal	> 5.0–20.0 x ULN if baseline was normal; > 5.0–20.0 x baseline if baseline was abnormal	> 20.0 x ULN if baseline was normal; > 20.0 x baseline if baseline was abnormal
Aspartate aminotransferase	> ULN–3.0 x ULN if baseline was normal; 1.5–3.0 x baseline if baseline was abnormal	> 3.0–5.0 x ULN if baseline was normal; > 3.0–5.0 x baseline if baseline was abnormal	> 5.0–20.0 x ULN if baseline was normal; > 5.0–20.0 x baseline if baseline was abnormal	> 20.0 x ULN if baseline was normal; > 20.0 x baseline if baseline was abnormal
Bilirubin	> ULN–1.5 x ULN if baseline was normal; > 1.0–1.5 x baseline if baseline was abnormal	> 1.5–3.0 x ULN if baseline was normal; > 1.5–3.0 x baseline if baseline was abnormal	> 3.0–10.0 x ULN if baseline was normal; > 3.0–10.0 x baseline if baseline was abnormal	> 10.0 x ULN if baseline was normal; > 10.0 x baseline if baseline was abnormal