Chemotherapy in the Setting of Severe Liver Dysfunction in Patients with Metastatic Colorectal Cancer

Table 2

List of chemotherapeutic and biologic agents for patients with mCRC.

	Pharmacokinetics	Metabolism	Comments
5-Fluorouracil (5-FU) [13]	16 minutes (range 8–20 minutes); Excreted via lung (as CO2) and urine	Hepatic by dihydropyrimidine dehydrogenase (DPD) to active metabolites 5-fluoroxyuridine monophosphate (F-UMP) and 5-5-fluoro-2’-deoxyuridine-5’-O-monophosphate (F-dUMP)	Limited data in patients with total bilirubin > 5, may be treated with weekly infusion without adjustment [4].
Oxaliplatin [14]	Protein bound; 0.43 to 16.8 hours (distribution) and 391 hours (terminal); Urinary excretion	Nonenzymatic	No apparent alteration in clearance or toxicity in patients with severe liver dysfunction [3, 15, 16].
Irinotecan [17]	SN-38 protein bound; irinotecan 6–12 hours; SN-38 ~10–20 hours; Excreted via urine 11–20% and via biliary tract	Hydrolyzed in the liver to active metabolite SN-38 which is further metabolized by glucuronidation by UDP-glucuronosyltransferase 1-1 (also known as UGT1A1)	In patients with varying degrees of liver dysfunction, severe side effects, poor tolerability, and overall worsening of PS were noted. [2, 18, 19]
TAS-102 [10, 20]; combination drug consisting of alpha,alpha,alpha-trifluorothymidine (FTD) and thymidine phosphorylase inhibitor (TPI)	Readily absorbed; FTD 1.4 hours, TPI 1.7–2.1 hours; Limited urinary excretion FTD; TPI 29% excreted via urine	FTD undergoes hepatic metabolism, TPI minimal hepatic metabolism	Phase-I studies in patients with hepatic impairment are ongoing.
Regorafenib [21]	for the drug 28 hours (14 to 58 hours; some metabolites may take longer for excretion, 32 to 70 hours)	Hepatic by CYP3A4 and UGT1A9	Severe drug induced liver injury has been reported with the use of drug; its use in patients with liver dysfunction would generally be avoided and requires close monitoring of liver function tests.
Monoclonal antibodies [5]	long: days to weeks	No liver metabolism/clearance	Generally acceptable to use if there are no other contraindications.

Anti-VEGF antibodies (bevacizumab/aflibercept) and antiepidermal growth factor (EGFR) antibodies (panitumumab/cetuximab) [1].