Version May 2024
INTRODUCTION — Patients undergoing chemotherapy for cancer using molecularly targeted agents, which take advantage of molecular abnormalities that drive cancer progression, require careful assessment of liver function both prior to and during therapy. Potential interactions between the liver and chemotherapy fall into two categories:
●Direct chemotherapy-induced hepatotoxicity.
●Potentiation of pre-existing liver disease, including viral hepatitis. Altered hepatic drug metabolism due to underlying liver disease can result in higher or more persistent drug levels, thereby causing increased systemic toxicity (particularly myelosuppression) or worsening of liver function because of chemotherapy-induced hepatotoxicity. The majority of these agents are extensively metabolized in the liver, and require dose reduction in the setting of baseline hepatic impairment.
The interrelationship between the liver and molecularly targeted agents used for cancer therapy agents is reviewed here. General aspects of drug-induced hepatotoxicity with cancer chemotherapy is presented elsewhere, as is the interrelationship between the liver and conventional cytotoxic chemotherapy agents used for cancer therapy, and hepatotoxicity associated with checkpoint inhibitor immunotherapy (ipilimumab, pembrolizumab, nivolumab), as used for advanced melanoma and other solid tumors. (See "Chemotherapy hepatotoxicity and dose modification in patients with liver disease: Conventional cytotoxic agents", section on 'General aspects of chemotherapy-induced hepatotoxicity' and "Chemotherapy hepatotoxicity and dose modification in patients with liver disease: Conventional cytotoxic agents", section on 'Specific cytotoxic agents' and "Hepatic, pancreatic, and rare gastrointestinal complications of immune checkpoint inhibitor therapy".)
General aspects of drug metabolism and patterns of hepatic injury are discussed separately, as are the issues of reactivation of hepatitis B (HBV) viral infection in patients treated with immunosuppressive therapy, screening for hepatitis B and C virus infection in patients initiating systemic anticancer treatment (including with molecularly targeted agents), and viral prophylaxis for those patients at risk for HBV reactivation. (See "Drugs and the liver: Metabolism and mechanisms of injury" and "Drug-induced liver injury" and "Hepatitis B virus reactivation associated with immunosuppressive therapy" and "Chemotherapy hepatotoxicity and dose modification in patients with liver disease: Conventional cytotoxic agents", section on 'HBV screening and management'.)
SPECIFIC AGENTS
Fibroblast growth factor receptor inhibitors — Erdafitinib, futibatinib, infigratinib, and pemigatinib are inhibitors of fibroblast growth factor receptor (FGFR); they are approved for treatment of advanced malignancies that harbor certain FGFR mutations. (See "Treatment of metastatic urothelial carcinoma of the bladder and urinary tract", section on 'FGFR mutation positive' and "Systemic therapy for advanced cholangiocarcinoma", section on 'FGFR inhibitors for FGFR fusion-positive tumors'.)
Transient increases in liver function tests (LFTs; alanine aminotransferase [ALT], aspartate transaminase [AST], alkaline phosphatase) can be seen in up to 50 percent of patients receiving these drugs; they are grade 3 or worse (table 1) in only 0 to 1 percent of cases. There are no recommendations for dose adjustment in the setting of pre-existing liver dysfunction for erdafitinib or futibatinib; however, the United States Prescribing Information for infigratinib recommends lower initial starting doses for patients with mild (total bilirubin any level above the upper limit of normal (ULN) to 1.5 X ULN, or AST above ULN) or moderate (total bilirubin >1.5 to 3 X ULN with any AST) impairment, and the United States Prescribing Information for pemigatinib recommends lower initial starting doses for those with severe impairment (total bilirubin >3 X ULN).
Kinase inhibitors
Axitinib — Axitinib is a tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor (VEGFR) 1, 2, and 3. Clinical trials in advanced renal cell carcinoma have demonstrated up to a 22 percent incidence of elevated aminotransferases with <1 percent being grade 3 or 4. Axitinib in combination with avelumab or with pembrolizumab can cause hepatotoxicity with higher than expected frequencies of grade 3 and 4 transaminase elevations.
Baseline assessment and routine monitoring of liver function studies during therapy is recommended for all patients receiving axitinib. When used in combination with avelumab or pembrolizumab, the United States Prescribing Information for axitinib recommends treatment interruption for ALT or AST ≥3 X ULN but <10 X ULN without concurrent total bilirubin ≥2 X ULN, and discontinuing the drug for ALT/AST increase to >3 X ULN with concurrent total bilirubin ≥2 X ULN or any ALT/AST increase >10 X ULN.
Patients with Child-Pugh class A liver dysfunction require no baseline dose adjustment, while a reduced starting dose is recommended for all patients with pre-existing moderate hepatic impairment (Child-Pugh class B cirrhosis). No data are available on axitinib use in patients with Child-Pugh class C liver dysfunction.
ALK inhibitors — Alectinib, brigatinib, ceritinib, crizotinib, and lorlatinib are orally active inhibitors of anaplastic lymphoma kinase (ALK); all are approved for treatment of advanced or metastatic non-small cell lung cancer if the tumor contains a characteristic EML4-ALK fusion oncogene, and all are associated with hepatotoxicity. (See "Anaplastic lymphoma kinase (ALK) fusion oncogene positive non-small cell lung cancer".)
●Alectinib – In phase II studies, grade 3 or 4 elevations in AST or ALT were reported in 3.6 and 4.8 percent of patients treated with alectinib; grade 3 elevations in bilirubin developed in 2.8 percent [1]. The majority of cases occurred during the first two months of treatment. The United States Prescribing Information recommends monitoring of LFTs every two weeks during the first three months of therapy and then once monthly and as clinically indicated, with more frequent testing in patients who develop transaminase and bilirubin elevations. Treatment should be temporarily withheld for grade 3 or 4 transaminase elevation with total bilirubin ≤2 times ULN or total bilirubin >3 times ULN, and permanently discontinued for grade 3 or 4 transaminase elevation with total bilirubin >2 times ULN.
A reduced initial dose is recommended for those with pre-existing severe hepatic impairment (Child-Pugh class C cirrhosis) [2].
●Brigatinib – In the most recent update of the phase III first-line ALTA trial, AST elevations occurred in 72 percent of patients treated with brigatinib and they were grade 3 or 4 in 4.5 percent; ALT elevations occurred in 52 percent and were grade 3 or 4 in 54 percent [3].
The United States Prescribing Information for brigatinib recommends monitoring LFTs during treatment, especially during the first three months, and provides guidance for management for drug-induced hepatotoxicity during treatment. A reduced initial dose is recommended for those with pre-existing severe hepatic impairment (Child-Pugh class C cirrhosis).
●Ceritinib – Drug-induced hepatotoxicity is more common and severe in patients treated with ceritinib than the other ALK inhibitors. In one study, elevations in ALT occurred in 80 percent of 255 treated patients, and levels were greater than five times ULN (grade ≥3) in 27 percent; by contrast, 15 percent had elevated bilirubin levels, only 1 percent were severe [4]. The United States Prescribing Information for ceritinib recommends monitoring LFTs (AST, ALT, and serum bilirubin) at least monthly during therapy, with more frequent testing if transaminases are elevated. Specific guidelines are provided for dose adjustments in the setting of severe hepatotoxicity.
A reduced initial dose is recommended for those with pre-existing severe hepatic impairment (Child-Pugh class C cirrhosis) [4].
●Crizotinib – In phase II studies, grade 3 or 4 abnormal LFTs occurred in 4 to 7 percent of patients receiving crizotinib; they were mostly reversible and asymptomatic, and did not recur with lower doses. However, treatment had to be permanently discontinued in 4 of 255 (1.6 percent) of cases.
The United States Prescribing Information recommends that treatment be withheld for grade 3 or 4 aminotransferase elevation as long as serum bilirubin is ≤1.5 times the upper limit of normal (ULN); permanent discontinuation is advised for grade 2 or higher aminotransferase elevation if serum bilirubin is >1.5 times ULN.
Patients with moderate to severe pre-existing liver dysfunction (initial AST or serum total bilirubin elevation >1.5 times ULN) should receive a reduced initial dose of crizotinib [5].
●Lorlatinib – Severe hepatotoxicity has occurred when lorlatinib is administered concurrently with rifampin, a strong inducer of CYP3A, and concurrent administration should be avoided. Whether this interaction occurs with other strong CYP3A inducers (table 2) is unclear. The recommended dose has not been established for patients with pre-existing moderate to severe hepatic impairment, and guidance is not provided in the United States Prescribing Information for lorlatinib.
Bosutinib — Bosutinib is a multitargeted tyrosine kinase inhibitor that targets Bcr-Abl and the SRC family of tyrosine kinases. Clinical trials in patients with chronic myelogenous leukemia demonstrated transaminase elevation in 14 to 17 percent [6]. The United States Prescribing Information recommends monthly assay of transaminases for the first three months of treatment and as clinically indicated thereafter. Guidelines for dose reduction in patients with baseline liver impairment and for those who develop severe hepatotoxicity during therapy are available [6].
BRAF inhibitors — There are three available orally administered inhibitors of some mutated forms of BRAF, vemurafenib, dabrafenib, and encorafenib. These drugs are often used in combination with a MEK inhibitor, and with combination regimens, hepatotoxicity may be due to either of the drugs. (See 'MEK inhibitors' below.)
●Vemurafenib – Vemurafenib is approved for treatment of metastatic melanoma with a V600E BRAF mutation. (See "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations", section on 'Toxicities of BRAF and MEK inhibitors'.)
In early clinical trials, grade 3 to 4 abnormalities in LFTs (GGT, transaminases, bilirubin) occurred in 2 to 12 percent of patients. The United States Prescribing Information for vemurafenib recommends monitoring of liver enzymes and bilirubin before initiation and monthly during treatment.
Vemurafenib does not undergo appreciable hepatic metabolism, and adjustment to the starting dose is not needed for patients with pre-existing mild to moderate liver impairment. Due to lack of data, the drug should be used with caution in patients with severe liver impairment.
●Dabrafenib – Dabrafenib is approved as a single agent or in combination with trametinib for treatment of BRAF mutation-positive melanomas, non-small cell lung cancer, and anaplastic thyroid cancer. (See 'MEK inhibitors' below and "Adjuvant and neoadjuvant therapy for cutaneous melanoma", section on 'Adjuvant dabrafenib plus trametinib' and "Personalized, genotype-directed therapy for advanced non-small cell lung cancer", section on 'BRAF mutations' and "Anaplastic thyroid cancer", section on 'BRAF V600E mutation identified' and "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations", section on 'Dabrafenib plus trametinib' and "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations", section on 'Toxicities of BRAF and MEK inhibitors'.)
Increases in transaminases or alkaline phosphatase develop in approximately one-half of treated patients, but they are severe in fewer than 6 percent. The United States Prescribing Information does not contain a specific recommendation for periodic monitoring of LFTs.
Hepatic metabolism and biliary secretion are the primary route of elimination, and patients with moderate to severe hepatic impairment (serum bilirubin >1.5 times ULN, and any elevation in AST) may have increased exposure. However, an appropriate starting dose has not been established for patients with pre-existing hepatic impairment according to the United States Prescribing Information.
●Encorafenib – Encorafenib is approved in combination with the MEK inhibitor binimetinib for treatment of BRAF mutation-positive advanced melanoma, and in combination with cetuximab for BRAF mutation-positive advanced colorectal cancer. (See "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations", section on 'Encorafenib plus binimetinib' and "Systemic therapy for nonoperable metastatic colorectal cancer: Approach to later lines of systemic therapy", section on 'RAS wild-type, BRAF mutated tumors'.)
Encorafenib is primarily metabolized by the liver. There are no recommended dose modifications for pre-existing moderate to severe hepatic impairment.
Increases in GGT are reported in approximately 50 percent of treated patients, and grade 3 or 4 in 11 percent. Approximately 15 to 25 percent develop elevations in transaminases, with grade 3 or 4 transaminase elevations seen in up to 10 percent.
Liver function testing should be monitored before and during treatment with encorafenib. The dose of encorafenib should be withheld, reduced, or permanently discontinued based on the severity of the hepatoxicity.
Bruton tyrosine kinase inhibitors — Ibrutinib, acalabrutinib, zanubrutinib, and pirtobrutinib are orally active inhibitors of Bruton tyrosine kinase, a mediator of the B-cell receptor signaling pathway that inhibits malignant B-cell survival. The use of these drugs for the treatment of mantle cell lymphoma and chronic lymphocytic leukemia is discussed separately.
●(See "Treatment of relapsed or refractory chronic lymphocytic leukemia", section on 'Pirtobrutinib'.)
These drugs are metabolized in the liver, and significant increases in exposure are expected in patients with hepatic impairment. The following dose adjustments are recommended based on the United States Prescribing Information:
●Ibrutinib – Reduce the initial dose in patients with mild or moderate liver impairment (Child-Pugh class A or B). Avoid use in patients with severe liver impairment (Child-Pugh class C) [7].
●Acalabrutinib – No dose modification is recommended for patients with mild or moderate impairment. Avoid use in patients with severe hepatic impairment [8].
●Zanubrutinib – No dose modification is recommended in patients with mild to moderate hepatic impairment. Reduce the initial dose in patients with severe hepatic impairment [9].
●Pirtobrutinib – No dose adjustment is recommended in patients with mild, moderate, or severe hepatic impairment [10].
CDK 4/6 inhibitors — Ribociclib, palbociclib, and abemaciclib are orally active inhibitors of cyclin-dependent kinase (CDK) 4/6 that are approved for treatment of hormone-receptor-positive metastatic breast cancer.
In clinical trials, 7 to 10 percent of patients treated with ribociclib had grade 3 or 4 elevations in transaminases; approximately 1 percent had elevations in total bilirubin. The United States Prescribing Information for ribociclib recommends performing LFTs at baseline, every two weeks for the first two cycles, at the beginning of each subsequent four cycles, and as clinically indicated thereafter; dose modification guidelines are available in the event of hepatotoxicity during therapy.
Ribociclib undergoes extensive hepatic metabolism. A reduced starting dose is recommended in patients with moderate to severe hepatic impairment (Child-Pugh class B/C).
Palbociclib also undergoes extensive hepatic metabolism; the United States Prescribing Information for palbociclib recommends a reduced initial starting dose (from 125 to 75 mg daily) for individuals with severe hepatic impairment (Child-Pugh class C cirrhosis) but not for those with mild to moderate impairment.
Abemaciclib is also associated with transient elevations in transaminases during therapy and is hepatically metabolized. The United States Prescribing Information for abemaciclib lists specific guidelines for dose reduction during therapy based upon hepatotoxicity and also recommends a reduced starting dose in patients with pre-existing severe (Child-Pugh class C) hepatic impairment.
Dasatinib — Dasatinib is a tyrosine kinase inhibitor that targets Bcr-Abl, KIT, the platelet-derived growth factor receptor (PDGFR), and the SRC family of tyrosine kinases. Dasatinib may cause hepatoxicity with elevated bilirubin, AST, and ALT.
The United States Prescribing Information for dasatinib suggests monitoring liver function tests prior to starting treatment, and then monthly or as clinically indicated [11]. Liver function tests should be monitored when dasatinib is administered with chemotherapy as hepatoxicity has been observed with the combination. Patients with baseline liver dysfunction do not require initial dose modification. Grade 3 and 4 aminotransferase elevations typically respond to a brief treatment interruption or dose reduction for recurrent hepatoxicity.
Erlotinib and gefitinib — Erlotinib and gefitinib are small molecule inhibitors of the tyrosine kinase domain of the epidermal growth factor receptor (EGFR). Both are primarily metabolized in the liver by the cytochrome P450 system.
Hepatic dysfunction decreases clearance of erlotinib [12]. Patients with an elevated total serum bilirubin (above the institutional ULN) or Child-Pugh class A, B, or C cirrhosis (table 3) should be closely monitored during treatment. Hepatic failure and hepatorenal syndrome, occasionally fatal, have been reported, particularly in patients with pre-existing moderate to severe hepatic impairment [13,14] and in elderly/frail patients on multiple medications [15]. Even if baseline levels are normal, erlotinib should be interrupted or discontinued for total bilirubin >3 times ULN, or for aminotransferase elevation ≥5 times ULN during treatment.
Although the United States Prescribing Information for erlotinib does not provide specific guidelines, some clinicians recommend a reduced initial dose (75 rather than 150 mg) in patients with AST ≥3 times ULN or serum direct bilirubin 1 to 7 mg/dL [12]. Others suggest that a reduced starting dose is not needed in those with moderate hepatic impairment (ie, Child-Pugh class B cirrhosis (table 3)) [16].
Gefitinib uncommonly causes increased aminotransferases [17]. Compared with erlotinib, there is less information on gefitinib in patients with liver dysfunction. A report of two cirrhotic patients with lung cancer noted no untoward effects using every other day administration [18]. However, the United States Prescribing Information does not recommend dose reduction, even for patients with moderate to severe liver dysfunction.
Imatinib — Imatinib is a tyrosine kinase inhibitor targeting Bcr-Abl and KIT that is metabolized by cytochrome P450; as a result, other drugs metabolized through this pathway may increase imatinib concentrations, potentially increasing its hepatotoxicity [19].
Imatinib is hepatically metabolized, and the effects of hepatic impairment on pharmacokinetics was addressed in a report of 84 patients with a variety of cancers receiving imatinib at doses ranging from 100 to 800 mg daily [20]. Mild or moderate hepatic impairment did not influence exposure to imatinib or its metabolites, but patients with severe haptic impairment had increased drug exposure. The United States Prescribing Information suggests a 25 percent dose reduction in those with severe hepatic impairment (total bilirubin >3 to 10X ULN with any transaminase elevation).
Imatinib causes elevations in serum LFTs (AST/ALT, alkaline phosphatase, total bilirubin) in 15 to 20 percent of patients receiving the drug, most commonly during the first 12 months of treatment [21-23]. Hepatotoxicity can be severe, and fatal acute hepatic necrosis has been reported [22]. At least one report indicates that treatment with corticosteroids led to resolution of hepatic abnormalities and permitted the resumption of therapy [23]. For patients who develop hepatotoxicity during therapy (elevations of total bilirubin >3 times ULN or transaminases >5 times ULN), the United States Prescribing Information recommends withholding treatment until bilirubin <1.5 times ULN and transaminases <2.5 times ULN, then resuming treatment with a reduced dose (eg, if current dose is 400 mg daily, reduce dose to 300 mg daily).
Lapatinib, neratinib, and tucatinib — Lapatinib and neratinib are dual tyrosine kinase inhibitors of both human epidermal growth factor receptor (HER) 2/neu (erbB-2) and EGFR, which is also called erbB-1; neratinib also inhibits HER4. Tucatinib inhibits HER2 and HER3.
The use of these drugs as subsequent-line therapy in HER2-positive advanced breast cancer and HER2-positive metastatic colorectal cancer is discussed separately. (See "Systemic treatment for HER2-positive metastatic breast cancer", section on 'Patients who require second- or later-line treatment' and "Systemic therapy for nonoperable metastatic colorectal cancer: Approach to later lines of systemic therapy", section on 'RAS wild-type, HER2 overexpressors'.)
●Lapatinib – Lapatinib is associated with severe, potentially fatal hepatotoxicity (mainly aminotransferase elevation). In one study of 154 patients, approximately 40 percent of patients developed hepatotoxicity of any grade, and it was severe (grade 3 or 4) in one-half of cases [24]. Major histocompatibility complex (MHC) variants appear to influence the risk of liver injury with lapatinib [25,26]. In one study, inheritance of two specific human leukocyte antigen (HLA) alleles (HLA-DRB1*07:01 and HLA-DQA1*02:01, study frequency 22 percent) had the highest levels of association with ALT elevation during lapatinib therapy (odds ratio 14, 95% CI 6-31) [25]. Overall, carriage of one of the high-risk alleles had a low positive predictive value. Among the lapatinib-treated patients, the risk for ALT elevation >5 times ULN by 13 weeks was 7.7 percent for carriers of these high-risk HLA alleles versus 0.5 percent in noncarriers. However, the risk was cumulative over time, and by 400 days of exposure, individuals with the HLA-DRB1*07:01 allele had a 15 percent probability of having ALT >3 times ULN compared with 1.1 percent for noncarriers.
Taken together, these data suggest a possible immune basis for lapatinib-induced hepatotoxicity and support a potential role for genotyping to identify those who are at highest risk. However, at present, routine genotyping for the presence of one of these high-risk alleles is not yet a standard approach for patients being considered for lapatinib therapy.
Lapatinib is extensively metabolized in the liver. The United States Prescribing Information suggests dose reduction for patients with severe hepatic impairment (Child-Pugh class C) who are treated with lapatinib in combination with capecitabine; for lapatinib in combination with letrozole, they recommend dropping the initial lapatinib dose from 1500 to 1000 mg daily (table 4) [27]. LFTs should be monitored at least every four to six weeks during therapy, and the drug discontinued for severe changes in liver function (ALT/AST >3 times ULN, bilirubin >2 times ULN).
●Neratinib – Neratinib has also been associated with hepatotoxicity as manifested by increased liver enzymes. In the adjuvant ExteNET trial, 10 percent of patients experienced an ALT increase ≥2 times ULN, 5 percent of patients experienced an AST increase ≥2 times ULN, and 1.7 percent of patients experienced an AST or ALT elevation >5 times ULN (grade ≥3).
The United States Prescribing Information for neratinib suggests monitoring total bilirubin, AST, ALT, and alkaline phosphatase prior to starting treatment, monthly for the first three months of treatment, and then every three months. Tests are also recommended in patients experiencing grade 3 diarrhea or any signs or symptoms that may reflect hepatotoxicity (eg, worsening fatigue, nausea, vomiting, right upper quadrant tenderness, fever, rash, or eosinophilia).
Similar to lapatinib, neratinib is extensively metabolized in the liver. Patients with severe pre-existing hepatic impairment (Child-Pugh class C cirrhosis) have experienced a reduction in neratinib clearance and an increase in serum concentrations of the drug; reduced initial doses are recommended in this population.
●Tucatinib – Tucatinib has also been associated with hepatotoxicity, manifested by elevated transaminases and/or bilirubin. The United States Prescribing Information for tucatinib recommends assessing ALT, AST, and bilirubin prior to starting therapy, every three weeks during treatment, and as clinically indicated [28]. The drug should be interrupted, dose-reduced, or permanently discontinued based on the severity.
Tucatinib is also extensively metabolized in liver. A lower starting dose is recommended for individuals with pre-existing severe liver disease (Child-Pugh class C cirrhosis).
Lenvatinib — Lenvatinib is a multitargeted tyrosine kinase inhibitor targeting VEGFR1, 2, and 3, as well as FGFR1, 2, 3, and 4; PDGFR alpha; KIT; and RET. In clinical trials involving patients with differentiated thyroid cancer, grade 3 or 4 aminotransferase elevation has been observed in 4 to 5 percent of treated patients. The United States Prescribing Information recommends monitoring liver function before initiation of the drug, every two weeks for the first two months, then at least monthly thereafter. The starting dose should be reduced in patients with pre-existing severe hepatic impairment (Child-Pugh class C cirrhosis (table 3)).
MEK inhibitors — Cobimetinib, trametinib, and binimetinib are MEK inhibitors that are approved for the treatment of melanoma, typically combined with a BRAF inhibitor. While no dose adjustment is recommended for liver dysfunction for cobimetinib and trametinib, the United States Prescribing Information for binimetinib does suggest a reduced initial dose for moderate or severe hepatic impairment (total bilirubin >1.5 times ULN and any AST elevation).
All three drugs can cause hepatotoxicity, and baseline and periodic monitoring of liver function is recommended in the United States Prescribing Information for all three drugs. (See "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations", section on 'Encorafenib plus binimetinib'.)
MET inhibitors — Mesenchymal-epithelial transition (MET) is a tyrosine kinase receptor for hepatocyte growth factor. Two specific inhibitors of MET, capmatinib and tepotinib, are approved for treatment of advanced non-small cell lung cancer (NSCLC) with specific MET mutations that lead to MET exon 14 skipping. (See "Personalized, genotype-directed therapy for advanced non-small cell lung cancer", section on 'MET abnormalities'.)
●Capmatinib – Increases in ALT/AST occurred in 13 percent of patients treated in the GEOMETRY mono-1 trial; it was grade 3 or 4 in 6 percent [29,30]. The median time to onset was 1.4 months.
LFTs (including ALT, AST, and total bilirubin) should be monitored prior to the start of capmatinib, every two weeks during the first three months of treatment, then once a month or as clinically indicated, with more frequent testing in patients who develop increased transaminases or bilirubin. The United States Prescribing Information for capmatinib includes specific recommendations for managing the drug in the event of hepatotoxicity.
●Tepotinib – In a pooled safety population, increased ALT/AST occurred in 13 percent of treated patients; it was grade 3 or 4 in 4.2 percent. Median time to onset was 30 days [31].
LFTs (including ALT, AST, and total bilirubin) should be monitored prior to the start of tepotinib, every two weeks during the first three months of treatment, then once a month or as clinically indicated, with more frequent testing in patients who develop increased transaminases or bilirubin. The United States Prescribing Information for tepotinib includes specific recommendations for managing the drug in the event of hepatotoxicity.
Nilotinib — Nilotinib is a multitargeted tyrosine kinase inhibitor that targets Bcr-Abl, KIT, and PDFGR. Metabolism is primarily hepatic, and exposure is increased in patients with impaired hepatic function. The United States Prescribing Information recommends initial dose reduction in patients with even mild hepatic impairment (defined as Child-Pugh class A cirrhosis) (table 3). The specified dose reductions are outlined in the table (table 4).
Pazopanib — Pazopanib is an oral agent that targets multiple tyrosine kinases including VEGFR, PDGFR, and KIT. In clinical trials, severe hepatotoxicity (increased aminotransferases and total bilirubin) has been seen in approximately 18 percent of patients; 2 of 977 died with both disease progression and hepatic failure [32].
The United States Prescribing Information for pazopanib recommends that LFTs be monitored before initiation of treatment and at weeks 3, 5, 7, 9, 12, and 16, and then as clinically indicated. Treatment should be interrupted in the event of hepatotoxicity; permanent discontinuation is advised if ALT elevations >3 times ULN occur concurrently with bilirubin elevations >2 times ULN.
Genetic factors may influence susceptibility to pazopanib-related hepatotoxicity:
●Inheritance of certain polymorphisms in the uridine diphospho-glucuronosyltransferase (UGT) 1A1 enzyme that cause Gilbert syndrome (the UGT1A1*28 allele) seem to be associated with pazopanib-induced hyperbilirubinemia [33,34]. These results support the view that some instances of isolated hyperbilirubinemia in these patients represent a benign manifestation of Gilbert syndrome, and that continuation of pazopanib monotherapy is reasonable in this setting. Genetic testing for the UGT1A1*28 allele is available (the Invader UGT1A1 Molecular Assay), but most clinicians do not routinely test patients prior to therapy; instead, they follow LFTs closely as per the United States Prescribing Information. (See "Gilbert syndrome".)
●An association between carriage of HLA-B*57:01 and ALT elevation was also suggested in a genome-wide association study of 1188 pazopanib-treated patients with cancer from eight clinical trials [35]. Given that HLA-B*57.01 functions as an immune receptor, these findings raise the possibility of an immune-mediated mechanism for pazopanib-associated hepatotoxicity in some patients. However, it is premature to conclude that pretreatment testing for HLA-B*57:01 is warranted to identify those who are at higher risk of hepatotoxicity.
Pazopanib is metabolized by the liver, and dose reduction may be needed for patients with moderate to severe liver dysfunction. In a phase I study of 98 patients with hepatic dysfunction treated with pazopanib, the maximum tolerated dose in patients with moderate hepatic impairment (total bilirubin >1.5 to 3 times ULN regardless of the ALT value) was 200 mg per day [36]. United States Prescribing Information suggests dose reduction to 200 mg per day for total bilirubin 1.5 to 3 times ULN and that the drug not be used in patients with more severe liver impairment.
Pexidartinib — The oral kinase inhibitor pexidartinib is approved for patients with advanced tenosynovial giant cell tumor (TGCT) that is not amenable to resection. (See "Treatment for tenosynovial giant cell tumor and other benign neoplasms affecting soft tissue and bone", section on 'Pexidartinib (CSF1R inhibitor)'.)
Pexidartinib can cause serious and potentially fatal liver injury:
●In one trial, 3 of 61 patients (5 percent) who received pexidartinib for TGCT developed serious liver injury, defined as ALT or AST ≥3 times ULN with total bilirubin ≥2 times ULN. After treatment discontinuation, AST, ALT, and bilirubin levels improved to <2 times ULN within one to seven months [37].
●In a pooled analysis of 140 patients with TGCT treated with the drug across four clinical studies, 133 (95 percent) experienced a hepatic adverse reaction, but the vast majority (128, 91 percent) had reversible, low-grade, dose-dependent isolated transaminase elevations without elevated alkaline phosphatase [38]. Five patients had mixed or cholestatic liver injury, all of whom recovered from one to seven months following discontinuation. Of the non-TGCT population, 5 of the 658 patients experienced serious hepatic adverse effects, two irreversible.
Given the risk for hepatotoxicity, pexidartinib is available only through a restricted program under a Risk Evaluation and Mitigation Strategy. The United States Prescribing Information recommends to avoid pexidartinib in patients with pre-existing active liver or biliary disease, including those with isolated increased ALT, AST, bilirubin (either total or direct, unless due to Gilbert's syndrome), and alkaline phosphatase [39]. However, if the benefits are felt to outweigh the risks, there are recommendations for initial dose reduction in those with moderate hepatic impairment.
The drug should be administered with a low-fat meal (no more than approximately 11 to 14 grams of total fat). Taking pexidartinib with a high-fat meal increases drug exposure by 100 percent and may increase the risk of hepatotoxicity.
LFTs (AST, ALT, total and direct bilirubin, alkaline phosphatase, and gamma-glutamyl transferase [GGT]) should be assessed at baseline and monitored weekly for the first eight weeks, every two weeks for the next month, and every three months thereafter. Pexidartinib may need to be withheld, dose reduced, or permanently discontinued based on the severity of liver dysfunction. The United States Prescribing Information includes recommended dose modifications for treatment-emergent hepatotoxicity [39].
We avoid the use of strong inducers of cytochrome P450 3A (CYP3A) with pexidartinib, which reduce its efficacy (table 2). We also avoid the use of moderate or strong inhibitors of CYP3A and uridine diphospho-glucuronosyltransferase (UGT; eg, probenecid) as these particular classes of drugs increase its plasma concentrations and hepatoxicity risk. However, if the concurrent use of a CYP3A or UGT inhibitor cannot be avoided, then we reduce the initial dose of pexidartinib per guidelines from the United States Prescribing Information [39].
PI3K inhibitors — Of the oral inhibitors of phosphoinositide-3 kinase (PI3K) that are approved in the United States, hepatotoxicity is described with idelalisib and duvelisib:
●Idelalisib – Idelalisib is an oral inhibitor of PI3K delta that is approved for treatment of relapsed chronic lymphocytic leukemia, follicular lymphoma, and small lymphocytic lymphoma. Serious and potentially fatal hepatotoxicity has occurred in patients treated with idelalisib, predominantly within the first 12 weeks of treatment, and affecting approximately 14 percent of treated patients. Abnormalities have generally been reversible with dose interruption. Close monitoring of LFTs, especially during the first three months of treatment, is recommended. Dose modification guidelines for hepatotoxicity during therapy are available in the US Prescribing Information for idelalisib.
Systemic exposure to idelalisib is increased in patients with pre-existing hepatic insufficiency [40]; however, safety and efficacy data are not available in patients with baseline moderate to severe hepatic dysfunction, as these patients were excluded from clinical studies. Patients with baseline hepatic impairment should be closely monitored for signs of toxicity.
●Duvelisib – Duvelisib is an oral dual inhibitor of PI3K delta and gamma that is approved for treatment of chronic lymphocytic leukemia. (See "Treatment of relapsed or refractory chronic lymphocytic leukemia".)
Transaminase elevations are reported in up to 20 percent of patients treated with duvelisib; 3 percent of patients have grade 3 or 4 elevations (table 1) [41,42]. Elevations in serum bilirubin are seen less often. The United States Prescribing Information for duvelisib recommends monitoring hepatic function during treatment and provides recommendations for dose reduction or treatment discontinuation for grade 3 or 4 transaminase elevations.
Ponatinib — Ponatinib targets Bcr-Abl, VEGFR, PDGFR, FGFR, the SRC family of kinases, KIT, RET, TIE2, and FLT3; it is approved in the United States for treatment of refractory chronic myelogenous leukemia. Ponatinib may result in elevations in ALT, AST, or both, and fatal acute liver failure has been described, sometimes within one week of starting therapy [43]. LFTs should be evaluated at baseline, and at least monthly during therapy.
Hepatic elimination is the main route of excretion for ponatinib. Patients with any degree of pre-existing hepatic dysfunction (Child-Pugh class A, B, or C) are at increased risk for adverse reactions, and a reduced initial dose is recommended in the United States Prescribing Information.
Pralsetinib — Pralsetinib is a kinase inhibitor of wild-type RET, and oncogenic RET mutations and fusions; it is used to treat RET fusion-positive non-small cell lung cancer. (See "Overview of the initial treatment of advanced non-small cell lung cancer", section on 'Other mutations'.)
Elevations in AST (69 percent, including grade 3 or 4 in 5 percent) and ALT (69 percent, including grade 3 or 4 in 5 percent) are frequent in patients treated with pralsetinib, and the median time to development is 15 to 22 days. The United States Prescribing Information for pralsetinib recommends monitoring liver function tests every two weeks for the first three months, and monthly thereafter; recommendations are available for dose modification in the event of severe toxicity.
Regorafenib — Regorafenib is a small molecule kinase inhibitor that targets VEGFR1, 2, and 3 in addition to RET, KIT, PDGFR alpha and beta, FGFR1 and 2, and several other membrane-bound and intracellular kinases that are involved in normal cellular function and in pathologic processes. It has been approved in the United States for treatment of metastatic colorectal cancer in patients previously treated with multiple cytotoxic and molecularly targeted therapies. (See "Systemic therapy for nonoperable metastatic colorectal cancer: Approach to later lines of systemic therapy", section on 'Regorafenib'.)
Fatal drug-induced liver injury occurred in 0.3 percent of 1100 patients treated with regorafenib on clinical trials [44]. In the placebo-controlled CORRECT trial, fatal hepatic failure occurred in 1.6 percent of patients treated with regorafenib for metastatic colorectal cancer (versus 0.4 percent in the placebo group). Biopsy, where available, has shown hepatocyte necrosis with lymphocytic infiltration.
The United States Prescribing Information for regorafenib recommends baseline LFTs (ALT, AST, bilirubin) prior to initiating therapy and at least every two weeks during the first two months of treatment, and monthly thereafter. Dose adjustment is not recommended for pre-existing mild to moderate hepatic impairment (Child-Pugh class A or B cirrhosis), but use of the drug is not recommended in those with Child-Pugh class C disease. For hepatotoxicity during treatment, the manufacturer recommends withholding dose until recovery for grade 3 AST or ALT elevations (table 1) and to resume therapy at a reduced dose if potential benefit outweighs risk. Regorafenib should be discontinued permanently for re-occurrence of AST/ALT >5 times ULN despite dose reduction, or for any AST/ALT >20 times ULN, or for AST/ALT >3 times ULN plus bilirubin >2 times ULN. Given the incidence of severe and potentially fatal hepatotoxicity, some clinicians initiate therapy at a lower dose and titrate to goal dose while monitoring liver function closely.
Ruxolitinib — Ruxolitinib is an inhibitor of Janus associated kinases (JAK1 and JAK2), which is used for treatment of primary myelofibrosis, polycythemia vera, and refractory acute graft versus host disease. (See "Treatment of acute graft-versus-host disease", section on 'Ruxolitinib' and "Polycythemia vera and secondary polycythemia: Treatment and prognosis".)
Ruxolitinib is mainly metabolized in liver by CYP3A4, and to a lesser extent, CYP2C9. Systemic drug exposure is increased in patients with pre-existing liver dysfunction, and there are potential drug-drug interactions with both CYP3A4 inhibitors and inducers (table 2). The United States Prescribing Information for ruxolitinib contains recommendations for dose modification in the setting of pre-existing hepatic impairment that vary according to the indication for usage, and for concomitant use of strong CYP3A4 inhibitors that cannot be avoided.
Selpercatinib — Selpercatinib is a kinase inhibitor approved to treat non-small cell lung cancer, medullary thyroid cancer and other types of thyroid cancers, and other advanced solid tumors that have an alteration (mutation or fusion) in a specific gene (RET or "rearranged during transfection"). (See "Personalized, genotype-directed therapy for advanced non-small cell lung cancer", section on 'RET rearrangements' and "Medullary thyroid cancer: Systemic therapy and immunotherapy", section on 'Selpercatinib'.)
Selpercatinib is predominantly metabolized in the liver by CYP3A4. The United States Prescribing Information recommends a reduced initial dose for patients with severe pre-existing hepatic impairment (total bilirubin >3 to 10 times ULN and any AST elevation). No dose modification is recommended for patients with mild (total bilirubin ≤ULN with AST greater than ULN, or total bilirubin >1 to 1.5 times ULN with any AST) or moderate (total bilirubin >1.5 to 3 times ULN with any AST elevation) hepatic impairment.
In clinical trials, approximately one-half of treated patients had elevations in transaminases during therapy with selpercatinib; they were grade 3 or 4 in approximately 10 percent. Median time to onset was approximately four weeks. Elevations in total bilirubin occurred in approximately one-fourth; they were grade 3 or 4 in 2 percent. The United States Prescribing Information recommends monitoring ALT and AST at baseline, every two weeks during the first three months, then monthly thereafter and as clinically indicated. Withhold, reduce dose, or permanently discontinue treatment based on severity.
Sotorasib — Sotorasib is an inhibitor of the RAS GTPase family; it is approved for treatment of advanced non-small cell lung cancer with a RAS G12C mutation. (See "Personalized, genotype-directed therapy for advanced non-small cell lung cancer", section on 'RAS mutations'.)
Sotorasib has been linked to drug-induced liver injury and hepatitis. In a review of adverse reactions in 204 patients treated in one study, 25 percent had some form of hepatotoxicity, and approximately one-half of cases were grade 3 or 4 [45]. The most common abnormalities were increased AST, ALT, or alkaline phosphatase. The United States Prescribing Information for sotorasib recommends monitoring LFTs every three weeks for the first three months of therapy, and then once monthly as clinically indicated. Dose modification guidelines are provided based upon the severity of hepatotoxicity.
Sorafenib — Sorafenib is a potent small molecule inhibitor of multiple tyrosine kinases, including VEGFR. Sorafenib-induced hepatitis is characterized predominantly by a hepatocellular pattern of liver damage with significant increases in transaminases that may result in hepatic failure and death. Uncommon elevations in the international normalized ratio (INR) or hyperbilirubinemia may occur [46,47]. Some have suggested that hyperbilirubinemia correlates with high levels of systemic drug exposure and that both are linked to inheritance of a UGT1A1*28 allele, which is associated with reduced enzymatic activity and Gilbert syndrome [48].
LFTs and the international normalized ratio (INR) should be monitored regularly during treatment. The United States Prescribing Information for sorafenib recommends discontinuation of the drug for grade 3 or higher ALT increase, or greater than three times the ULN (3X ULN) for either ALT or AST with a bilirubin greater than 2X ULN, or for any grade increase in alkaline phosphatase in the absence of known bone pathology and grade 2 or worse bilirubin elevation, or INR ≥1.5.
There are conflicting data on the need for dose reduction in patients with pre-existing liver dysfunction:
●Results from a phase I study suggest that dose reduction to 200 mg twice a day is required in patients with a bilirubin 1.5 to 3 times ULN, and that the drug cannot be tolerated with more severe hyperbilirubinemia [46].
●On the other hand, at least one study in patients treated for advanced hepatocellular cancer concluded that dose reduction is not necessary in patients with mild to moderate aminotransferase elevation (≥1.8 times ULN).
United States Prescribing Information for sorafenib recommends no dose adjustment for pre-existing Child-Pugh class B impairment and makes no recommendation for those with Child-Pugh class C cirrhosis (table 3). The tolerance of sorafenib in patients with liver disease is addressed elsewhere. (See "Systemic treatment for advanced hepatocellular carcinoma", section on 'Sorafenib'.)
Sunitinib — Sunitinib is another potent small molecule inhibitor of multiple tyrosine kinases including VEGFR. Hepatotoxicity has been observed in clinical trials, which may result in liver failure (7 of 2281 patients, 0.3 percent); fatalities have been reported [49]. Liver function should be monitored prior to and during treatment. The drug should be interrupted for bilirubin levels >3 times ULN, AST/ALT >5 times ULN and not restarted until resolution.
As with sorafenib and pazopanib, sunitinib-associated hyperbilirubinemia has been linked to inheritance of a UGT1A1*28 allele, which is associated with reduced enzymatic activity and Gilbert syndrome [34].
Tivozanib — Tivozanib is a potent small molecule inhibitor of VEGFR1, 2, and 3, as well as KIT and PDGFR-beta; it is extensively metabolized in the liver, predominantly by CYP3A4. The United States Prescribing Information for tivozanib recommends a lower initial starting dose in patients with pre-existing moderate hepatic impairment (serum total bilirubin >1 to 1.5 ULN with any AST); recommended dosage for more severe hepatic impairment has not been established.
Vandetanib — Vandetanib is another orally active inhibitor of several tyrosine kinases including RET, VEGFR, and EGFR. In clinical trials involving patients with medullary thyroid cancer and lung cancer, aminotransferase elevation has been observed in over 20 percent of treated patients [50,51]. Vandetanib is partially metabolized in the liver. The United States Prescribing Information recommends avoiding use of vandetanib in patients with moderate and severe hepatic impairment (Child-Pugh class B or C cirrhosis (table 3)), as safety and efficacy have not been established.
mTOR inhibitors
Everolimus — Everolimus is an orally administered inhibitor of the mammalian target of rapamycin (mTOR). Metabolism is primarily hepatic, and exposure is increased in patients with mild to moderate hepatic impairment (defined by the US Food and Drug Administration [FDA] as Child-Pugh class A or B cirrhosis (table 3)) [52]. The United States Prescribing Information recommends a 25 percent dose reduction for patients with Child-Pugh class A cirrhosis being treated for breast cancer, renal cell cancer, and pancreatic neuroendocrine tumor, and a 50 percent dose reduction for Child-Pugh class B cirrhosis; for those with more severe hepatic impairment in whom the potential benefit outweighs risk, a maximum daily dose of 2.5 mg is recommended. There are different recommendations for patients receiving the drug for subependymal giant cell tumor [53].
Temsirolimus — Temsirolimus, another mTOR inhibitor, also undergoes hepatic metabolism. The United States Prescribing Information recommends a dose reduction to 15 mg weekly in patients with mild hepatic impairment (bilirubin >1 to 1.5 times ULN or AST greater than the ULN) and that the drug not be administered to patients with serum bilirubin >1.5 times ULN.
Ado-trastuzumab emtansine — Ado-trastuzumab emtansine (T-DM1) is an antibody-drug conjugate that incorporates the HER2-targeted agent trastuzumab with the cytotoxic microtubule inhibitor DM1. It is approved for advanced breast cancer in patients previously exposed to trastuzumab and taxanes. (See "Systemic treatment for HER2-positive metastatic breast cancer".)
Serious hepatotoxicity has been reported, including liver failure and death, in patients treated with T-DM1. The typical pattern is a transient increase in ALT and AST; elevations in serum total bilirubin occur less commonly. Hepatic function should be assessed at baseline and prior to each dose. Dose adjustment is recommended for grade 3 or higher transaminase or bilirubin elevation (table 1) [54].
In clinical trials of T-DM1, cases of nodular regenerative hyperplasia (now termed idiopathic noncirrhotic portal hypertension [including nodular regenerative hyperplasia]) were identified from liver biopsies in 3 from a total of 884 treated patients [54]. Idiopathic noncirrhotic portal hypertension is a rare condition whose overall incidence is unknown. The diagnosis should be considered in patients who develop otherwise unexplained portal hypertension that is confirmed by biopsy. Drug discontinuation is advised. (See "Noncirrhotic portal hypertension", section on 'Pathophysiology' and "Noncirrhotic portal hypertension", section on 'Idiopathic noncirrhotic portal hypertension/Porto-sinusoidal vascular disease'.)
Anti-CD-20 therapies and HBV reactivation — Multiple reports have documented a significantly increased incidence of hepatitis B (HBV) reactivation in patients with current or past HBV infection who are receiving certain types of myelosuppressive systemic chemotherapy, notably anti-CD20 therapies (ie, rituximab, ofatumumab, and obinutuzumab) used for certain hematologic conditions [55-57]. HBV reactivation can result in hepatitis (33 to 100 percent), liver failure (10 to 13 percent) and death (3 to 5 percent) [55,56]. Between 17 and 55 percent of individuals with past or chronic HBV infection who are treated with one of these agents may experience reactivation unless they receive antiviral prophylaxis.
These patients are considered at very high risk for reactivation if they are HBsAg positive. (See "Hepatitis B virus reactivation associated with immunosuppressive therapy", section on 'HBsAg-positive' and "Hepatitis B virus reactivation associated with immunosuppressive therapy", section on 'Very high risk'.)
Given the particularly high risk of HBV reactivation, the United States Prescribing Information for all three drugs includes boxed warning information concerning screening for HBV for all patents initiating treatment with these agents, and prophylactic treatment of all who are positive for either HBsAg or anti-HBc. In addition, monitoring for reactivation is recommended during therapy and for several months following completion of therapy. If reactivation occurs, treatment should be stopped, and appropriate therapy should be initiated for HBV.
Brentuximab — Brentuximab vedotin is an immunotoxin comprised of a CD30-directed monoclonal antibody linked to the antitubulin agent monomethyl auristatin E (MMAE). It is approved for treatment of refractory Hodgkin lymphoma and anaplastic large cell lymphoma. (See "Treatment of relapsed or refractory classic Hodgkin lymphoma" and "Treatment of relapsed or refractory peripheral T cell lymphoma", section on 'Brentuximab'.)
Severe and potentially fatal hepatotoxicity has been reported with brentuximab. The risk may be increased in those with pre-existing liver disease. Transaminases and serum bilirubin should be monitored during therapy.
Moderate (Child-Pugh class B) or severe (Child-Pugh class C) hepatic impairment increases the likelihood of severe adverse reactions and death in patients receiving brentuximab. The United States Prescribing Information recommends avoidance of the drug in these patients.
Elotuzumab — Elotuzumab is an immunostimulatory monoclonal antibody directed against the SLAMF7 molecule that is present on myeloma cells; it is approved in conjunction with lenalidomide and dexamethasone for treatment of relapsed lymphoma. (See "Multiple myeloma: Treatment of first or second relapse", section on 'Elotuzumab, lenalidomide, dexamethasone (ERd)'.)
Elevations in liver enzymes (ALT/AST, total bilirubin, alkaline phosphatase) were reported in 2.5 percent of patients treated with elotuzumab plus lenalidomide and dexamethasone, as compared with 0.6 percent of those treated with chemotherapy alone [58]. The United States Prescribing Information recommends periodic monitoring of liver enzymes and at least temporary discontinuation of the drug for grade ≥3 hepatotoxicity (table 1).
Enfortumab vedotin — Enfortumab vedotin is a nectin-4-directed monoclonal antibody microtubule inhibitor (MMAE) drug conjugate that is approved for metastatic refractory urothelial cancer. (See "Treatment of metastatic urothelial carcinoma of the bladder and urinary tract", section on 'Investigational agents'.)
The United States Prescribing Information for enfortumab suggests avoiding the drug in patients with moderate to severe hepatic impairment. Although enfortumab has not been directly studied in patients with hepatic impairment, this recommendation was based on data suggesting a higher frequency of grade 3 or worse adverse reactions and deaths with other antibody-drug conjugates that contain MMAE in the setting of moderate (Child-Pugh class B) or severe (Child-Pugh class C) hepatic impairment (table 3).
Gemtuzumab ozogamicin — Gemtuzumab ozogamicin is a CD33-directed antibody-drug conjugate that is indicated for the treatment of newly diagnosed CD33-positive acute myeloid leukemia in adults. Hepatotoxicity, including severe or fatal hepatic veno-occlusive disease (VOD, also known as sinusoidal obstruction syndrome), has been reported with the use of this drug, and the United States Prescribing Information recommends frequent monitoring for signs and symptoms of VOD during therapy, and that the drug be discontinued permanently if VOD develops.
Larotrectinib — Larotrectinib is a highly selective inhibitor of the neurotrophic tropomyosin receptor kinase (NTRK) gene that is approved for use in adults and children with solid tumors with an NTRK gene fusion that are either metastatic or where surgical resection is likely to result in severe morbidity, who have no satisfactory alternative treatments, or whose cancer has progressed following treatment. (See "TRK fusion-positive cancers and TRK inhibitor therapy".)
Elevations in transaminases occurred in nearly one-half of treated patients in a safety analysis of 176 patients with a variety of NTRK fusion-positive malignancies who received this agent, including a grade 3 increase in ALT or AST in 6 percent of patients [59].
Monitoring LFTs before and during treatment is warranted. Larotrectinib is withheld, reduced, or discontinued based on severity of the hepatotoxicity.
Drug clearance is reduced in patients with moderate (Child-Pugh class B) or severe (Child-Pugh class C) hepatic impairment, and a lower initial dose is warranted in these patients.
Niraparib — Niraparib is an inhibitor of poly ADP-ribose polymerase (PARP) that is approved for treatment of advanced gynecologic malignancies. In a small series of eight patients who received a single dose of niraparib in the setting of moderate hepatic impairment (total bilirubin >1.5 to 3 X ULN with any transaminase elevation), overall exposure to the drug was increased compared with those with normal hepatic function [60]. The United States Prescribing Information for niraparib recommends a lower starting dose of the drug in patients with moderate hepatic impairment, and that patients be monitored for hematologic toxicity. There is no information on whether other PARP inhibitors (ie, olaparib, rucaparib) should be dose reduced in the setting of moderate hepatic impairment.
Ramucirumab — Ramucirumab is a recombinant monoclonal antibody that binds to the VEGFR2, blocking receptor activation. It is approved in the United States for treatment of advanced gastric cancer. (See "Second and later-line systemic therapy for advanced unresectable and metastatic esophageal and gastric cancer", section on 'Ramucirumab with or without paclitaxel'.)
Clinical deterioration, manifested by worsening encephalopathy, ascites, or hepatorenal syndrome, has been reported among patients with Child-Pugh class B or C (table 3) cirrhosis who received the drug [61]. Ramucirumab should only be used in these patients if the potential benefits are judged to outweigh the risks.
Immune checkpoint inhibitors — Checkpoint inhibitors, immunomodulatory antibodies that are used to enhance the immune system, have substantially improved the prognosis for patients with advanced malignancy.
The primary targets for checkpoint inhibition include:
●Programmed cell death receptor 1 (PD-1) and programmed cell death ligand 1 (PD-L1) – Multiple antibodies against PD-1 and PD-L1 are in development and have shown great promise in multiple malignancies. Nivolumab, pembrolizumab, and cemiplimab all of which target PD-1, and atezolizumab, avelumab, and durvalumab, all of which target PD-L1, have been approved in various indications (eg, melanoma, renal cell carcinoma, non-small cell lung cancer, head and neck cancer, urothelial carcinoma, Hodgkin lymphoma, Merkel cell carcinoma, as well as microsatellite instability-high or mismatch repair deficient [dMMR] solid tumors).
●Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) – Ipilimumab, an anti-CTLA-4 antibody, is approved for use in patients with advanced melanoma, based on a significant improvement in overall survival. Another anti-CTLA-4 antibody (tremelimumab) is under development.
A wide range of immune-mediated adverse events are reported with all these agents, including severe and potentially fatal inflammation of the liver, although the risk appears to be lower overall with agents targeting the PD-1 pathway compared with ipilimumab. (See "Hepatic, pancreatic, and rare gastrointestinal complications of immune checkpoint inhibitor therapy", section on 'Hepatotoxicity'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Abnormal liver biochemical tests" and "Society guideline links: Drug-induced liver injury".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Drug-induced hepatitis (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Chemotherapy and liver function
•Patients undergoing chemotherapy for cancer using molecularly targeted agents, which take advantage of molecular abnormalities that drive cancer progression, require careful assessment of liver function both prior to and during therapy. Molecularly targeted agents used for cancer therapy may cause indirect or direct hepatotoxicity.
•Furthermore, abnormal liver function may alter drug metabolism and increase the risk of extrahepatic toxicity. (See 'Introduction' above.)
●Dose modification for pre-existing liver disease
•Guidelines on dose modification for patients with pre-existing hepatic disease are largely empiric. For some agents, including bosutinib, axitinib, lapatinib, tucatinib, erlotinib, nilotinib, pazopanib, ponatinib, ruxolitinib, selpercatinib, binimetinib, and temsirolimus, there is agreement on the need for dose adjustment (or avoidance altogether) in patients with pre-existing liver dysfunction in order to avoid excessive systemic toxicity (table 4). (See 'Specific agents' above.)
•There is less agreement on the need for dose reduction for other agents whose clearance is dependent upon liver metabolism, such as crizotinib, erlotinib, imatinib, and sorafenib. (See 'ALK inhibitors' above and 'Sorafenib' above and 'Erlotinib and gefitinib' above and 'Imatinib' above.)
●Screening for current or past infection with hepatitis B and C virus
•Infection with hepatitis B (HBV) or hepatitis C (HCV) is a common disorder that can be exacerbated with cytotoxic chemotherapy.
•Consistent with guidelines from the American Society of Clinical Oncology (ASCO), we endorse universal HBV screening for all patients beginning systemic anticancer therapy, including molecularly targeted therapy. The finding of chronic or past HBV infection requires HBV reactivation risk assessment to determine the need for antiviral prophylaxis. The recommended approach to HBV screening, monitoring, and antiviral prophylaxis is outlined in the algorithm (algorithm 1). Recommendations from ASCO and other expert groups for universal screening are discussed in detail elsewhere. (See "Chemotherapy hepatotoxicity and dose modification in patients with liver disease: Conventional cytotoxic agents", section on 'HBV screening and management'.)
Clinicians should also consider testing for chronic HCV infection prior to initiating potentially immunosuppressive chemotherapy, although the data are less compelling than for HBV testing. Patients with chronic HCV infection who are receiving chemotherapy should undergo serial monitoring of liver function tests, and if there is no dramatic change, continued chemotherapy treatment without dose modification is appropriate. (See "Chemotherapy hepatotoxicity and dose modification in patients with liver disease: Conventional cytotoxic agents", section on 'Hepatitis C'.)
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