Chemotherapy hepatotoxicity and dose modification in patients with liver disease: Conventional cytotoxic agents

INTRODUCTION — Patients undergoing chemotherapy for cancer using conventional cytotoxic agents, molecularly targeted agents, and immunotherapeutic agents, 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 preexisting liver disease, especially 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 interrelationship between the liver and cytotoxic chemotherapy agents is reviewed here. The interrelationship between the liver and molecularly targeted agents used for cancer therapy are discussed elsewhere, as is hepatotoxicity associated with checkpoint inhibitor immunotherapy, as used for advanced melanoma and other solid tumors. (See "Chemotherapy hepatotoxicity and dose modification in patients with liver disease: Molecularly targeted agents" and "Hepatic, pancreatic, and rare gastrointestinal complications of immune checkpoint inhibitor therapy", section on 'Hepatotoxicity'.)

General aspects of drug metabolism and patterns of hepatic injury are discussed separately, as is reactivation of hepatitis B (HBV) viral infection in patients treated with immunosuppressive therapy. (See "Drugs and the liver: Metabolism and mechanisms of injury" and "Drug-induced liver injury" and "Hepatitis B virus reactivation associated with immunosuppressive therapy".)

GENERAL ASPECTS OF CHEMOTHERAPY-INDUCED HEPATOTOXICITY

Mechanisms — Most hepatotoxic drug reactions are idiosyncratic and classified mechanistically either as immunologic (hypersensitivity) or metabolic [1]. These reactions typically are neither dose dependent nor predictable. (See "Drugs and the liver: Metabolism and mechanisms of injury", section on 'Mechanisms of drug-induced hepatotoxicity'.)

While the reaction to many chemotherapy drugs is manifested by hepatocellular injury, inflammation, and/or cholestasis, other agents cause endothelial damage or thrombosis leading to vascular complications such as hepatic veno-occlusive disease (VOD, also called hepatic sinusoidal obstruction syndrome [SOS]). (See 'Hepatic vascular injury' below.)

Liposomal drug formulations — Liposomal drug delivery systems have been utilized to improve the pharmacologic characteristics of chemotherapeutics and antibiotics, and improve drug delivery to optimal sites of action. Nevertheless, concerns have been raised about altered toxicity profiles with these preparations relative to non-encapsulated drug forms:

●In a case control study of patients undergoing hematopoietic cell transplant, use of liposomal amphotericin B (L-AMB) was associated with a higher rate of elevated liver enzymes compared with conventional amphotericin B deoxycholate (AMB-D) [2]. However, an autopsy study of 64 patients treated before death with either L-AMB or amphotericin B lipid complex (ABLC) failed to reveal any clear histologic evidence of hepatotoxicity in either group, despite well-characterized elevations in liver enzymes with administration of these medicines [3]. These data suggest that elevated liver enzymes associated with liposomal drug formulations such as amphotericin B may not reflect severe histologic injury.

●On the other hand, animal studies have suggested that sterically stabilized liposomal encapsulation of 6-mercaptopurine (6-MP) is associated with decreased hepatoxicity compared with conventional liposomal formulations [4].

As liposomal drug delivery approaches become more common and diverse, patterns of hepatotoxicity may be altered.

Hepatic vascular injury — SOS, previously called VOD, is a pattern of liver injury that is caused by nonthrombotic obliteration of small intrahepatic veins by subendothelial fibrin. SOS is associated with congestion and potentially fatal necrosis of centrilobular hepatocytes.

SOS occurs most frequently in patients undergoing hematopoietic cell transplantation. Most cases are thought to be drug-induced, and the drugs most commonly implicated are those that undergo hepatic metabolism. (See "Hepatic sinusoidal obstruction syndrome (veno-occlusive disease) in adults", section on 'Introduction' and "Hepatic sinusoidal obstruction syndrome (veno-occlusive disease) in adults".)

SOS has occasionally been reported with non-myeloablative doses of dacarbazine (DTIC) [5-11], including patients treated with ABVD (doxorubicin, bleomycin, vinblastine, DTIC) for Hodgkin lymphoma [12,13], and with dactinomycin [11], 6-thioguanine (6-TG) or 6-MP [14,15], and azathioprine (AZ) [16,17].

Oxaliplatin is associated with a dose-dependent pattern of hepatic sinusoidal injury, similar to SOS, which can be identified radiographically by the development of splenomegaly resulting from an increase in portal venous pressure [18-22]. The manifestations of this toxicity are best described in the adjuvant setting, where approximately 45 percent of patients who have received six months of treatment with an oxaliplatin-containing regimen develop splenomegaly with resultant reductions in platelet counts that tend to normalize within approximately two years [18]. Most of these patients do not develop a clinical picture of cirrhosis over time. (See "Noncirrhotic portal hypertension", section on 'Idiopathic noncirrhotic portal hypertension/Porto-sinusoidal vascular disease'.)

The potential clinical impact of hepatic sinusoidal injury is best described in patients undergoing hepatic metastasectomy for colorectal cancer liver metastases; patients who receive preoperative chemotherapy with regimens containing oxaliplatin have increased bleeding risk and postoperative morbidity. Findings at the time of liver resection include steatosis, hepatic vascular injury, and nodular regenerative hyperplasia (now termed idiopathic noncirrhotic portal hypertension [including nodular regenerative hyperplasia]). Because of this injury pattern, it is generally recommended that the duration of neoadjuvant therapy be limited to the fewest number of cycles needed to render patients resectable. Concomitant administration of bevacizumab may protect against the development of oxaliplatin-induced hepatic sinusoidal injury, although the data are mixed. (See "Potentially resectable colorectal cancer liver metastases: Integration of surgery and chemotherapy", section on 'Post-treatment assessment and duration of neoadjuvant therapy'.)

A similar pattern of hepatic vascular injury with steatosis is reported in patients receiving preoperative therapy with combinations of irinotecan and FU prior to the resection of liver metastases. As with oxaliplatin combinations, it is generally recommended that the duration of neoadjuvant therapy be limited to the fewest number of cycles needed to render patients resectable. (See 'Irinotecan and liposomal irinotecan' below and "Potentially resectable colorectal cancer liver metastases: Integration of surgery and chemotherapy", section on 'Post-treatment assessment and duration of neoadjuvant therapy'.)

Irradiation plus chemotherapy — Although radiation to the liver is itself hepatotoxic, otherwise tolerable doses of radiation therapy to the right upper quadrant can induce severe hepatic injury when combined with systemic doses of normally nonhepatotoxic chemotherapeutic agents. This has been described most often in patients treated concurrently with hepatic radiation and vincristine [23,24], doxorubicin [25], and dactinomycin. (See 'Dactinomycin' below.)

In an illustrative series, 35 patients with lymphoma received concurrent monthly vincristine and relatively low-dose liver irradiation (total dose, 15 to 25 Gy) [23]. Ten of 35 patients developed severe hepatotoxicity (aspartate transaminase [AST] greater than three times normal, clinical evidence of liver failure, one fatal), and nine had moderate toxicity.

Reactivation or exacerbation of radiation-induced hepatic damage is a likely mechanism since all of these drugs have been associated with a radiation "recall" reaction in previously irradiated tissues. (See "Cutaneous adverse effects of conventional chemotherapy agents", section on 'Radiation recall dermatitis and radiation enhancement'.)

Clinical presentation and diagnosis — The clinical presentation of chemotherapy-related hepatotoxicity can range from asymptomatic biochemical abnormalities to an acute illness with jaundice that resembles viral hepatitis [26].

The severity of liver injury is primarily assessed by measurement of gamma-glutamyl transpeptidase (GGT), the serum aminotransferases (AST and alanine aminotransferase [ALT]), bilirubin, and alkaline phosphatase. The pattern of abnormalities on these tests is more informative than elevation of any individual test. Elevation of aminotransferases (AST, ALT) typically indicates hepatocellular injury, while increases in bilirubin and alkaline phosphatase suggest cholestasis. (See "Overview of liver biochemical tests".)

Standardized criteria have been developed by the National Cancer Institute (NCI) and World Health Organization (WHO) to quantify or grade the severity of treatment-related abnormalities in the liver function tests (LFTs) in patients undergoing chemotherapy (table 1).

The differential diagnosis includes progressive tumor, exacerbation of coexisting hepatic disease, reactivation of chronic viral hepatitis, and adverse effects of other drugs which produce similar clinical features and abnormalities in the LFTs [27,28]. The distinction between drug-induced hepatotoxicity due to chemotherapy and other causes of liver injury can be difficult. Features suggesting toxicity due to chemotherapy include lack of prior illness, clinical symptoms or biochemical abnormalities developing after drug administration, and improvement after discontinuation of the cytotoxic agent. (See 'Impact of preexisting liver disease' below.)

Testing for hepatitis A, B, C, and sometimes cytomegalovirus (CMV) is commonly sent to evaluate for infectious causes of elevated liver enzymes. Abdominal ultrasound or computed tomography (CT) may be needed to differentiate drug toxicity from biliary, vascular, or tumor-related conditions. A liver biopsy is seldom necessary to characterize or stage acute hepatotoxicity [29]. (See "Approach to the patient with abnormal liver biochemical and function tests" and "Approach to liver biopsy".)

Natural history — The natural history of chemotherapy hepatotoxicity is variable. Some agents cause reversible toxicity while others are associated with a progressive course that can lead to fibrosis or cirrhosis despite drug discontinuation. If the damage is reversible after withholding of the offending agent, toxicity will generally recur upon reintroduction of the offending agent. Dose reduction for subsequent courses or permanent discontinuation of the drug may be advised, depending on the specific agent, and the severity of the hepatotoxicity. If the reaction was immunologically based (eg, a true hypersensitivity reaction accompanied by rash, eosinophilia), rechallenge is usually not recommended. (See 'Dacarbazine' below.)

Impact of preexisting liver disease — Susceptibility to chemotherapy-induced liver injury may be increased by the presence of hepatobiliary metastases, immune compromise, chronic liver disease including viral/autoimmune hepatitis, nutritional deficiencies, or the use of parenteral nutrition.

Patients with a preexisting liver disease should undergo a full diagnostic workup prior to chemotherapy to elucidate the cause and severity of the liver disease. Therapy of any coexisting liver disorder should be optimized to minimize the potential for chemotherapy-induced complications. (See "Approach to the patient with abnormal liver biochemical and function tests".)

Clinical decision-making must incorporate the need for expedient treatment of the patient's malignancy. Some drugs will need to be avoided while dose reduction may be appropriate for other agents in patients with significant liver disease, regardless of its etiology (table 2).

Infection with hepatitis B (HBV) or hepatitis C (HCV) is a common disorder that can be exacerbated or reactivated with cytotoxic chemotherapy. Importantly, many people are unaware that they have a viral infection at the time of the diagnosis of cancer [30].

Hepatitis B — HBV infection with a high viral load prior to treatment is an adverse factor for survival and may be associated with a higher incidence of severe hepatitis during chemotherapy [31]. In addition, multiple reports have documented a significantly increased incidence of HBV reactivation in patients receiving certain types of myelosuppressive systemic chemotherapy, notably anti-CD20 therapies (ie, rituximab, ofatumumab, and obinutuzumab). Patients who are at high risk for HBV reactivation during chemotherapy with high-risk regimens such as these may benefit from prophylactic antiviral therapy. (See "Hepatitis B virus reactivation associated with immunosuppressive therapy", section on 'Very high risk' and "Chemotherapy hepatotoxicity and dose modification in patients with liver disease: Molecularly targeted agents", section on 'Anti-CD-20 therapies and HBV reactivation'.)

The magnitude of risk for less myelosuppressive chemotherapy regimens, as are used for treatment of solid tumors, has not been well established [32,33]. In a systematic review of 26 observational studies and randomized trials in patients with chronic or resolved HBV receiving chemotherapy for solid tumors, the risk of reactivation for patients with chronic HBV (ie, hepatitis B surface antigen [HBsAg] positive) ranged from 4 to 68 percent, with most studies reporting a reactivation risk greater than 10 percent [32]. For individuals with resolved HBV infection (defined as HBsAg negative, hepatitis B core antibody [anti-HBc] positive, HBV DNA negative), reactivation rates ranged from 0.3 to 9.0 percent. Antiviral therapy administered during chemotherapy reduced the risk of HBV reactivation by approximately 90 percent, and also reduced HBV-related hepatitis and the need for chemotherapy interruption. (See "Hepatitis B virus reactivation associated with immunosuppressive therapy", section on 'Who is at risk for HBV reactivation'.)

HBV screening and management — We agree with an updated year 2020 provisional clinical opinion from the American Society of Clinical Oncology, which endorses universal HBV screening for all patients beginning systemic anticancer therapy (cytotoxic chemotherapy, immunotherapy, molecularly targeted therapy) using three tests, hepatitis B surface antigen (HbSAg), hepatitis B core antibody (anti-HBc), total immunoglobulin (Ig) or IgG, and antibody to hepatitis B surface antigen (anti-HBs) [34]. The finding of chronic HBV (HbSAg-positive) or past HBV (HbSAg-negative and anti-HBc-positive) infection requires HBV reactivation risk assessment to determine the need for antiviral prophylaxis. Their recommended approach to HBV screening, monitoring, and antiviral prophylaxis, which is largely aligned with that of the American Association for the Study of Liver Disease (AASLD), is outlined in the algorithm (algorithm 1). Guidelines for risk stratification are also available from the American Gastroenterology Association (AGA) [35]. The AGA and the American Society of Clinical Oncology (ASCO)/AASLD guidelines differ regarding the level of risk for certain patients, in particular those who are HBsAg negative.

This position from ASCO reflects a change in the approach that was endorsed in 2015 (which recommended HBV screening of patients receiving chemotherapy only if they were at high risk for HBV infection or if highly immunosuppressive therapy was being used [eg, hematopoietic cell transplantation or use of an anti-CD20 agent such as rituximab, ofatumumab, or obinutuzumab]) [36], and is now concordant with recommendations from other groups, including the AASLD [37]. The change in recommendation was attributed to the publication of at least three large prospective cohort studies that provide strong, albeit indirect, evidence in support of universal HBV screening in patients receiving systemic therapy for cancer because of the risk of HBV reactivation, the fact that many individuals with newly diagnosed cancer and concurrent HBV have no identifiable risk factors for infection, and the greater efficiency of universal as opposed to risk-based screening [30,38,39]. A later update from the expert panel convened by ASCO provides strategies for practical implementation of universal screening in cancer centers and community-based clinics [40]. This subject is discussed in detail elsewhere. (See "Hepatitis B virus reactivation associated with immunosuppressive therapy".)

Hepatitis C — Clinicians should also consider testing for chronic hepatitis C virus 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 LFTs, and if there is no dramatic change, continued chemotherapy treatment without dose modification is appropriate. (See "Screening and diagnosis of chronic hepatitis C virus infection".)

Severe hepatitis from reactivation of HCV infection has been documented in case reports [41-43], but it seems to be less common than HBV reactivation [44], and the relationship between immunosuppressive chemotherapy and viral reactivation is less clear than for HBV.

In three large series of patients who had anti-HCV antibodies, treatment for hematologic malignancies was associated with mild LFT abnormalities in 18 percent or fewer [45-47]. In another report of 33 patients, 32 of whom had chronic disease as manifested by positivity for HCV RNA, transaminases increased in 55 percent; however, only one patient had a severe flare of underlying hepatitis [48]. Thus, although chemotherapy may be associated with elevations in LFTs in patients with HCV, this does not appear to be a major issue except for those with preexisting decompensated liver disease.

Infection with HCV does appear to increase the risk of developing SOS in patients undergoing high dose chemotherapy and hematopoietic stem cell transplantation. (See "Hepatic sinusoidal obstruction syndrome (veno-occlusive disease) in adults", section on 'Risk factors'.)

Dose reduction for patients with baseline hepatic impairment — Altered drug metabolism due to hepatic dysfunction can result in higher levels of systemic toxicity due to higher or more persistent drug levels. Knowledge of the pharmacokinetics of antineoplastic agents in patients with liver disease is incomplete and has generally been derived from small numbers of heterogeneous patients with only mild to moderate liver dysfunction. As a result, guidelines for dose adjustment in the setting of preexisting hepatic impairment are largely empirical (table 2).

Dose adjustments must be viewed in the appropriate clinical context. Patients with metastatic disease are rarely cured, and initial chemotherapy doses that could lead to excessive treatment-related toxicity should be avoided. On the other hand, if liver function tests (LFTs) are abnormal because of extensive liver metastases, and the hepatic metastases respond to treatment, doses can often be increased after the initial courses of therapy.

LiverTox — Additional information on chemotherapy-induced liver injury is available from the LiverTox, a collaborative effort of the Liver Disease Research Branch of the National Institute of Diabetes, Digestive and Kidney Diseases (NIDDK) and the National Library of Medicine (NLM). LiverTox is a freely accessible website that provides continuously updated comprehensive and evidence-based information about the clinical features of liver injury from drugs, dietary supplements, and herbal products along with a complete and annotated list of references.

SPECIFIC CYTOTOXIC AGENTS — In the following sections, both the hepatotoxicity of specific chemotherapy agents, and recommended dose modifications for patients with preexisting hepatic impairment are discussed. An important point is that most of these agents are used in combination regimens rather than as monotherapy.

Considerations for possibly greater hepatotoxicity using specific combination regimens and the potential difficulty with establishing which agent is responsible for the hepatotoxicity are outlined below. (See 'Combination chemotherapy regimens' below.)

Alkylating agents — As a group, alkylating agents are uncommonly associated with hepatotoxicity. Although the mechanism of liver damage associated with these agents is unclear, depletion of glutathione and oxidative injury have been implicated [49]. With the possible exception of cyclophosphamide and ifosfamide, patients receiving alkylating agents usually do not require dose reduction because of underlying liver disease.

Cyclophosphamide — Cyclophosphamide is metabolized by the liver to 4-hydroxycyclophosphamide, which is in equilibrium with its acyclic tautomeric form, aldophosphamide. In susceptible cells, nonenzymatic cleavage of aldophosphamide yields phosphoramide mustard and acrolein, which are thought to be the cytotoxic metabolites.

Despite its conversion in the liver to an active metabolite, cyclophosphamide is infrequently hepatotoxic. Abnormal LFTs attributed to the drug have only been reported occasionally, and this effect is probably due to an idiosyncratic reaction rather than direct toxicity [50-54].

In patients undergoing treatment for vasculitis, cyclophosphamide has been associated with liver necrosis when its administration was preceded by azathioprine (AZ) [55]. In two of the four affected patients, cyclophosphamide had previously been administered as a single agent without hepatic injury, suggesting that an interaction between the drugs was responsible for this toxicity. (See "General principles of the use of cyclophosphamide in rheumatic diseases".)

Increased toxicity has not been reported in patients with hepatic dysfunction [56,57]. Nevertheless, some clinicians recommend a 25 percent dose reduction in dose for patients with a serum bilirubin 3.1 to 5 mg/dL or aspartate transaminase (AST) greater than three times the upper limit of normal (ULN), and not giving the drug if the bilirubin is ≥5 mg/dL [58]. Specific dosing guidelines for patients with hepatic insufficiency are not available in the United States Prescribing Information.

Ifosfamide — Ifosfamide has been uncommonly associated with hepatotoxicity; in a total of 2070 patients from 30 studies of single-agent ifosfamide, the reported incidence of liver dysfunction was 3 percent [59,60].

Dose reductions are probably not necessary for patients with altered liver function. However, ifosfamide is extensively hepatically metabolized, and some clinicians recommend a 75 percent dose reduction (ie, 25 percent of goal dose administered) for patients with significant hepatic dysfunction (serum AST >300 int. unit/L or bilirubin >3 mg/dL) [58,61]. Specific dosing guidelines for patients with hepatic insufficiency are not available in the United States Prescribing Information.

Lurbinectedin — Lurbinectedin is an alkylating agent that is approved for refractory small cell lung cancer. Across clinical studies, approximately two-thirds of treated patients have some elevation in ALT, which are grade 3 or 4 in 6 percent; elevations in AST are reported in about one-fourth, and are grade 3 to 4 in about 4 percent of patients [62]. The United States Prescribing Information recommends monitoring LFTs prior to initiating treatment, periodically during treatment, and has specific guidelines for withholding or reducing the dose or permanently discontinuing based on severity.

Temozolomide — Temozolomide is an orally active alkylating agent used predominantly for the treatment of adults with primary brain tumors. Patients with mild to moderate hepatic dysfunction have similar pharmacokinetics compared to those with normal function, although patients with severe hepatic dysfunction have not been studied [63].

Fatal and severe hepatotoxicity has been reported in patients receiving temozolomide [64-67]. The United States Prescribing Information for temozolomide recommends that LFTs be performed at baseline, midway through the first cycle, prior to each subsequent cycle, and approximately two to four weeks after the last dose of temozolomide.

Other alkylating agents — Other alkylating agents generally are not dependent upon the liver for the metabolism and are not frequently associated with hepatotoxicity.

●Melphalan – Melphalan is rapidly hydrolyzed in plasma, and approximately 15 percent is excreted unchanged in the urine; the remainder is metabolized and excreted in stool. Although melphalan is not associated with hepatotoxicity at usual oral doses, transient LFT abnormalities have been reported with the higher doses used in the setting of hematopoietic stem cell transplantation [68,69]. (See "Preparative regimens for hematopoietic cell transplantation".)

●Chlorambucil – Chlorambucil rarely causes hepatotoxicity [70,71]. In one autopsy series of 181 patients with hematologic malignancies, three of six cases of cholestatic jaundice were attributed to chlorambucil [70]. In a second case report, drug-induced hepatotoxicity and skin rash recurred upon rechallenge with chlorambucil [71].

●Busulfan – Busulfan is rapidly cleared from the blood after intravenous administration and almost entirely excreted in the urine as methanesulfonic acid; hepatic metabolism is unimportant. At standard doses, busulfan rarely causes hepatic dysfunction, although it has been linked to some cases of cholestatic hepatitis [72,73].

Busulfan is a common component of preparative regimens for hematopoietic cell transplantation. In this setting, busulfan has been associated with hepatic sinusoidal obstruction syndrome (SOS). (See 'Hepatic vascular injury' above and "Hepatic sinusoidal obstruction syndrome (veno-occlusive disease) in adults".)

●Bendamustine – Bendamustine undergoes hepatic metabolism, and the United States Prescribing Information for bendamustine recommends that the drug not be administered to patients with preexisting moderate to severe hepatic impairment (transaminases ≥2.5 times ULN or total bilirubin ≥1.5 times ULN).

Nitrosoureas — The nitrosoureas carmustine (BCNU), lomustine (CCNU), and streptozocin appear to function as both alkylating and carbamoylating agents. Like other alkylating agents, nitrosoureas deplete hepatic stores of glutathione [74], which may increase the risk of oxidative injury.

Increases in LFTs occur in 20 to 25 percent of carmustine-treated patients [75,76], and the onset may be delayed up to four months following treatment. At conventional doses, LFT elevations are usually mild and revert to normal over a brief period, although fatalities have been reported. The hepatotoxic effects of CCNU are similar [77].

Streptozocin-induced hepatotoxicity is manifest primarily as hepatocellular injury and has been reported in 15 to 67 percent of treated patients [78,79]. These changes appear within a few days to weeks after treatment and are usually asymptomatic; rapid, complete resolution is the rule.

Although dosing adjustment may be necessary in patients with severe hepatic dysfunction, no guidelines have been published for any of the nitrosoureas. Specific dosing guidelines for patients with hepatic insufficiency are not available in the United States Prescribing Information. Hepatic function should be closely monitored during treatment.

Antimetabolites — The hepatotoxic potential of antimetabolites is variable. Hepatic metabolism plays an important role in the disposition of many drugs in this class, and dose reduction is frequently necessary in patients with liver dysfunction.

Cytarabine — Hepatotoxicity from cytarabine has been difficult to establish because it is used for treatment of leukemia, and these patients frequently undergo transfusions of blood products, are subject to infections, receive multiple medications, and are often not candidates for liver biopsy because of prolonged thrombocytopenia. Abnormal LFTs were reported in 37 of 85 leukemic patients receiving cytarabine in an early series, but many patients had preexisting LFT abnormalities, potentially confounding factors (eg, sepsis or hemolysis), or spontaneous resolution of biochemical abnormalities despite continuation of therapy [80].

In more contemporary reports, cytarabine infrequently causes histologically proven cholestasis [81,82]. Furthermore, transiently abnormal LFTs developed in 24 of 27 patients undergoing high-dose cytarabine by 72-hour continuous infusion in one series [83]. These effects are reversible and generally not dose-limiting [83-85].

The liver is the primary site for the detoxification of much of the administered dose of cytarabine. Doses should be reduced in patients with severe hepatic dysfunction in order to avoid an increased risk of treatment-related central nervous system toxicity [86]. (See "Overview of neurologic complications of conventional non-platinum cancer chemotherapy", section on 'Cytarabine'.)

Some clinicians recommend a 50 percent decrease in the dose in patients with any aminotransferase elevation [58]. However, this is not routinely done in potentially curative settings such as induction therapy for acute myelogenous leukemia. Specific dosing guidelines for patients with hepatic insufficiency are not available in the United States Prescribing Information.

Fluorouracil and capecitabine — Following intravenous administration, approximately 10 percent of administered fluorouracil (FU) is excreted unchanged in the urine, while the remainder is catabolized by dihydropyrimidine dehydrogenase (DPD), primarily in the liver. Both the toxicity and the antitumor effect are potentiated if catabolism is blocked by inhibition or inactivity of DPD. (See "Chemotherapy-associated diarrhea, constipation and intestinal perforation: pathogenesis, risk factors, and clinical presentation".)

Only rare reports of hepatotoxicity have been noted with FU [87]. More hepatotoxicity has been reported when FU is administered in combination with oxaliplatin and/or irinotecan. (See 'Hepatic vascular injury' above.)

Capecitabine is a fluoropyrimidine that is absorbed through the intestinal wall and then metabolized to the active metabolite, FU. Capecitabine causes hyperbilirubinemia, but this is sometimes attributable to hemolysis [88-90].

Because of the liver's role in the catabolism of intravenous FU, some clinicians recommend that doses be omitted in patients with liver failure (serum bilirubin >5 mg/dL) (table 2) [58]. Specific dosing guidelines for patients with hepatic insufficiency are not available in the United States Prescribing Information. By contrast, the pharmacology of capecitabine does not appear to be significantly affected by liver dysfunction [91], and dose reduction is not recommended in the United States Prescribing Information for capecitabine, although such patients should be monitored more frequently for adverse reactions.

Floxuridine — The FU metabolite floxuridine (fluorodeoxyuridine [FUdR]) is administered via the hepatic artery, usually for patients with isolated liver metastases from colorectal carcinoma. (See "Nonsurgical local treatment strategies for colorectal cancer liver metastases", section on 'Hepatic intra-arterial chemotherapy'.)

Intraarterial FUdR is associated with significant dose-limiting liver toxicity. Hepatic damage can be manifested in two ways [92-94]:

●Hepatocellular injury with increased AST/alanine aminotransferase (ALT), alkaline phosphatase, and serum bilirubin (hepatitis pattern).

●Biliary sclerosis, which results either from toxic effects on the biliary system or ischemic changes secondary to fibrosis of the pericholangitic venous plexus, both of which can result in stricture of the bile ducts [95-100]. The incidence ranges from 1 to 26 percent. Stricture of the intrahepatic or extrahepatic bile ducts is accompanied by elevated alkaline phosphatase and serum bilirubin.

FUdR-related hepatotoxicity appears to be both time and dose dependent. With rare exception, the hepatitis pattern improves with the temporary cessation of chemotherapy; however, secondary biliary sclerosis is irreversible (although treatable with stenting or dilatation) [101,102]. Two patterns of sclerosis may be evident: a diffuse pattern or a diffuse pattern with short segments of tight stricture, which are usually located in the proximal bile ducts.

LFTs should be checked at least weekly during therapy with intrahepatic arterial FUdR and drug administration discontinued (ie, the pump emptied) when hepatic toxicity becomes evident. Treatment should be restarted only when toxicity has resolved. Dose adjustment guidelines for FUdR in this setting have been published (table 3) [103]. Specific dosing guidelines for patients with hepatic insufficiency are not available in the United States Prescribing Information.

Gemcitabine — Gemcitabine is commonly associated with a transient rise in serum aminotransferases [104], but these are seldom of clinical significance; liver failure and death are very rare. There are case reports of rare fatal cholestatic hepatotoxicity [105].

There are limited and conflicting data about gemcitabine dosing in patients with preexisting liver dysfunction:

●In a prospective study of 18 patients with preexisting liver dysfunction who were enrolled into a phase I trial of escalating gemcitabine doses, giving gemcitabine to patients with preexisting hyperbilirubinemia (bilirubin levels >1.6 mg/dL) led to further deterioration in liver function [106]. The authors recommended an empiric initial dose reduction to 800 rather than 1000 mg/m² in this setting.

●On the other hand, a case series of seven patients who received at least one dose of gemcitabine (1000 mg/m²) when their serum bilirubin level was ≥4.5 mg/dL suggests that the full dose of gemcitabine can be given safely in patients with severe hepatic dysfunction [107]. Only one patient had a platelet count below 100,000 cells/microL that warranted reduction or withholding of a dose, and no patient had a further deterioration of liver function.

Similarly, a review of 29 patients receiving combined gemcitabine plus nanoparticle albumin-bound paclitaxel (nabpaclitaxel) for advanced pancreatic cancer (predominantly at full dose) who had an elevated bilirubin level did not reveal unexpected hematologic or hepatic toxicities, even among those with an initial total bilirubin level >5 mg/dL [108].

Specific dosing guidelines for patients with hepatic insufficiency are not provided in the United States Prescribing Information. However, it is probably prudent to utilize at least a 20 percent dose reduction for patients with hyperbilirubinemia of grade 2 or worse (>1.5 times ULN) (table 1) [109]. In the absence of toxicity, dose re-escalation could be considered.

Mercaptopurine — Hepatotoxicity related to the purine analog 6-mercaptopurine (6-MP) is most common if the usual daily dose of 2 mg/kg is exceeded. Two patterns have been noted: cholestatic liver damage and hepatocellular injury [110-114].

●In patients with cholestasis, histologic features include bland cholestasis, with minimal hepatic necrosis but significant cytologic atypia and disorganized hepatic cords [113,114].

●Hepatocellular injury typically occurs more than 30 days after treatment initiation. Moderate elevations in serum transaminases and alkaline phosphatase are accompanied by serum bilirubin levels between 3 and 7 mg/dL [111].

Changing the route of administration from oral to intravenous does not alter the pattern of hepatotoxicity [115]. Spontaneous resolution generally follows drug discontinuation.

Hepatotoxicity is thought to be a direct toxic effect of 6-MP because rechallenge does not necessarily shorten the latent period, and systemic manifestations of hypersensitivity (eg, rash, arthralgias, and eosinophilia) are usually not present [111]. However, in a series of 396 patients treated with 6-MP (1.5 mg/kg per day for an average of 60 months) for refractory inflammatory bowel disease, hepatitis developed in only one, and liver biopsy suggested a hypersensitivity reaction [116].

Severe and potentially fatal hepatotoxicity has also been described in patients treated with the combination of standard dose 6-MP and doxorubicin. (See 'Combination chemotherapy regimens' below.)

6-MP is metabolized in the liver by xanthine oxidase. Although specific guidelines are not available, dose reduction should be considered in patients with severe liver dysfunction to prevent drug accumulation.

Azathioprine — Azathioprine (AZ), a nitroimidazole derivative of 6-MP, is used as an immunosuppressive agent [117].

Hepatotoxicity is less frequent, milder, and less dose-dependent compared with 6-MP. Three different patterns of hepatotoxicity have been reported: hypersensitivity, an idiosyncratic cholestatic reaction, and presumed endothelial cell injury, with raised portal pressures, SOS, or peliosis hepatis [118]. Most reports of SOS have been observed in the setting of renal or hepatic transplantation. (See "Drug-induced liver injury" and 'Hepatic vascular injury' above.)

Cholestatic injury is characterized by an increased serum bilirubin and alkaline phosphatase, with moderate elevations in AST/ALT, and by variable degrees of parenchymal cell necrosis [118-120]. It is speculated that patients who develop hepatotoxicity convert AZ into 6-MP at an unusually rapid rate [121], an example of genetically-determined host metabolic idiosyncrasy.

Thioguanine — 6-thioguanine (6-TG) has been implicated in the development of hepatic SOS [14,122-124] and in a single case of peliosis hepatis [125]. An early report described jaundice among the potential adverse reactions [126]. 6-TG is rapidly and extensively metabolized in the liver. Thus, dose reduction or avoidance is recommended in patients with hepatic disease, although formal guidelines are lacking. (See 'Hepatic vascular injury' above.)

Methotrexate — Methotrexate (MTX) is a frequent component of combination chemotherapy regimens and is also used to treat a variety of nonmalignant disorders.

MTX-induced hepatotoxicity in patients receiving the drug parenterally for treatment of cancer usually takes the form of an acute transaminitis. This is most common in patients receiving high-dose MTX, which causes acute transaminitis in as many as 60 to 80 percent of patients; levels typically return to baseline within one to two weeks. (See "Therapeutic use and toxicity of high-dose methotrexate", section on 'Hepatotoxicity'.)

In contrast, patients undergoing chronic low-dose MTX therapy for rheumatoid arthritis or psoriasis are at risk for cirrhosis and fibrosis. This topic is discussed separately. (See "Hepatotoxicity associated with chronic low-dose methotrexate for nonmalignant disease".)

There are at least three case reports of hepatocellular carcinoma developing in patients with MTX-induced hepatic fibrosis, all of which were in children treated for acute lymphocytic leukemia (ALL), one in a patient heterozygous for alpha-1 antitrypsin deficiency [127-129]. These data suggest a potential for long-term carcinogenesis following treatment with MTX, at least in the rare patient who develops hepatic fibrosis. (See "Extrapulmonary manifestations of alpha-1 antitrypsin deficiency".)

In low doses, MTX is excreted mainly unchanged in the urine, while in high doses (such as are used to treat osteosarcoma and central nervous system [CNS] lymphoma), it is partially metabolized by the liver to 7-hydroxymethotrexate [130]. Specific dosing guidelines for hepatic insufficiency are not available in the United States Prescribing Information. Some clinicians suggest a 25 percent dose reduction for patients with either serum bilirubin 3.1 to 5 mg/dL or aminotransferases >3 times ULN, and omission of the drug for higher bilirubin levels [58]. Guidelines from Cancer Care Ontario recommend not using the drug if the total bilirubin level is >4 times ULN.

Any third-space fluid (eg, ascites, pleural effusions) will accumulate MTX and act as a reservoir for slow distribution into the plasma, increasing the risk of toxicity [131]. Large pleural or peritoneal effusions should be drained prior to therapy (particularly with high-dose MTX), and if this not possible, dose reduction is appropriate. (See "Therapeutic use and toxicity of high-dose methotrexate".)

Pemetrexed and pralatrexate — Pemetrexed and pralatrexate are novel folate analogs used in the treatment of lung cancer and refractory T-cell lymphomas, respectively. There are no published guidelines to guide dose reductions for patients with preexisting hepatic dysfunction. However, both drugs are potentially hepatotoxic, and guidelines for dose reduction for patients who develop grade 3 or 4 treatment-related hepatotoxicity during treatment are available in the United States Prescribing Information:

●For pemetrexed, reduce dose by 75 percent for bilirubin elevation >3 times ULN or transaminase elevation >5 times ULN.

●For pralatrexate, if total bilirubin >3 to 10 times ULN, or transaminases >5 to 20 times ULN, omit dose; after recovery to ≤grade 2 toxicity, decrease dose to 20 mg/m². For bilirubin >10 times ULN or transaminases >20 times ULN, discontinue treatment.

Antitumor antibiotics

Anthracyclines — The anthracyclines include doxorubicin (free and liposome-encapsulated), daunorubicin (free and liposome-encapsulated), epirubicin, and idarubicin. Doxorubicin is the most widely studied of these agents; the other compounds appear to be metabolized similarly and have a comparable pattern of toxicity.

Isolated case reports have suggested that doxorubicin can cause increased aminotransferases and hyperbilirubinemia [132]. However, these have generally been in the context of acute leukemia, where multiple factors may have contributed to hepatic dysfunction, or in patients undergoing right upper quadrant irradiation. (See 'Irradiation plus chemotherapy' above.)

Doxorubicin is extensively metabolized in the liver; approximately 80 percent of each dose is excreted in bile. Patients with cholestasis have delayed clearance of doxorubicin and its metabolites and greater systemic toxicity [133-135]. In contrast, patients with cirrhosis or isolated aminotransferase elevation may have normal drug clearance; excess toxicity has been reported from standard doses in some [136,137], but not all [138], studies.

Approaches to doxorubicin dosing in patients with impaired liver function are variable (table 2) [58,86,138-140]. The United States Prescribing Information for doxorubicin and pegylated liposomal doxorubicin recommend a 50 percent dose reduction for bilirubin 1.2 to 3 mg/dL, and a 75 percent dose reduction for bilirubin 3.1 to 5 mg/dL. Others suggest omission of the drug for bilirubin >5 mg/dL [58,109].

The applicability of these guidelines to weekly schedules of doxorubicin administration is uncertain. In one report, weekly administration was well tolerated in a woman with hepatic metastases from breast cancer and hyperbilirubinemia; treatment led to symptomatic improvement and normalization of LFTs [141].

The United States Prescribing Information for epirubicin and daunorubicin also recommends dose reduction for patients with serum bilirubin levels ≥1.2 mg/dL, and for epirubicin, a dose reduction for aminotransferase levels >2 times ULN (table 2). Others have suggested dose modification for epirubicin based upon serum AST and the desired drug exposure level, but measurement of drug levels is not a common practice [142].

Specific recommendations are not available for idarubicin, although the United States Prescribing Information suggests that a dose reduction be considered in patients with hepatic impairment.

Mitoxantrone — Mitoxantrone is an anthraquinone that is structurally related to the anthracyclines. In patients with leukemia, transient elevations in aminotransferase levels have been reported [143,144].

Total body drug clearance is reduced in patients with altered liver function, particularly hyperbilirubinemia [145-147]. Specific dosing guidelines for patients with hepatic insufficiency are not available in the United States Prescribing Information. Some clinicians recommend maintaining a standard dose of 14 mg/m² for moderate dysfunction (bilirubin 1.5 to 3.5 mg/dL) and reducing the dose to 8 mg/m² or avoidance of mitoxantrone for those with severe hepatic impairment and a bilirubin level >3.5 mg/dL [145].

Bleomycin — Approximately one-half of each administered dose of bleomycin is excreted unchanged in the urine; the remainder is inactivated by an aminopeptidase that is present in many tissues, including liver. Most studies report a low incidence of liver dysfunction in patients receiving bleomycin [148,149]. One review of over 1000 treated patients concluded that hepatotoxicity was inconsistently reported, and no specific pattern could be ascribed to this drug [148].

Mitomycin — Although hepatotoxicity is rare in patients treated with mitomycin, drug-induced alterations in LFTs [150] and hepatic SOS in the setting of high-dose therapy with hematopoietic cell transplantation [151] have been reported.

Mitomycin is metabolized predominantly in the liver; less than 10 percent is excreted unchanged in the urine, and biliary excretion also accounts for some elimination [152]. However, there are conflicting data regarding the influence of hepatic function on mitomycin clearance. In one report of 30 patients treated with mitomycin, there was no relationship between abnormal liver function, elimination half-life, and total body clearance [153]. Others have documented increased myelotoxicity in patients with preexisting hepatic dysfunction [154].

Specific dosing guidelines for patients with hepatic insufficiency are not available in the United States Prescribing Information. A number of different approaches have been utilized in patients with neoplasia-related hepatic dysfunction:

●In a series of women with advanced breast cancer and a predominance of visceral disease, initial mitomycin doses were empirically adjusted for liver dysfunction as follows: bilirubin 1.5 to 3 mg/dL, 50 percent of dose; bilirubin >3.1 mg/dL, 25 percent of dose [155].

●In a second report, the dose of mitomycin was empirically decreased by 50 percent in patients with a serum bilirubin >3 mg/dL or hepatic enzymes >3 times ULN [156].

Dactinomycin — Dactinomycin can cause a transient elevation in aminotransferases, which has most commonly occurred in children who received prior radiation therapy to the right upper quadrant. In this setting, greater than anticipated leukopenia and thrombocytopenia have also occurred, suggesting prolonged drug excretion due to radiation-induced hepatotoxicity [157]. (See 'Irradiation plus chemotherapy' above.)

Hepatotoxicity also occurs in unirradiated patients receiving dactinomycin and appears to be schedule dependent [158,159]. In one series of patients with Wilms tumor receiving dactinomycin either on five consecutive days or a double dose on a single day, hepatotoxicity developed in 13 versus 0 percent [158].

A hepatopathy-thrombocytopenia syndrome (HTS) has been described in approximately 1 percent of children treated with dactinomycin for Wilms tumor [11]. Hepatic veno-occlusive disease (VOD) is also reported. (See 'Hepatic vascular injury' above.)

Specific dosing guidelines for patients with hepatic insufficiency are not available in the United States Prescribing Information. A 50 percent reduction of dose has been recommended by some clinicians (table 2) [58].

Dacarbazine — There have been several reports of hepatic vascular toxicity in adults with melanoma who received single-agent dacarbazine (DTIC). Clinical findings include acute hepatic failure, shock, and death within a few days [160]. Histologically, acute thrombotic occlusions are present involving the small and medium-sized veins, unlike classic nonthrombotic SOS. Eosinophilia and eosinophilic infiltrates are frequently present, suggesting an idiosyncratic hypersensitivity mechanism rather than direct endoluminal damage [5,160]. (See 'Hepatic vascular injury' above.)

DTIC is metabolized by the hepatic microsomal pathway. Although patients with abnormal liver function may be at increased risk for hematologic toxicity [86], standard guidelines are not available for dose reduction in this setting.

Tubulin-acting agents — Cytotoxic drugs that act upon tubulin and microtubules require dose reduction in the setting of hepatic dysfunction.

Vinca alkaloids — Transient abnormalities in LFTs have been seen following treatment with both vincristine [161] and vinorelbine [162]. More severe hepatotoxicity is reported in patients who received vincristine plus concurrent irradiation. (See 'Irradiation plus chemotherapy' above.)

The vinca alkaloids are metabolized primarily by the liver, and the bile is the main route of excretion. Liver dysfunction that is severe enough to raise the serum alkaline phosphatase and alter biliary excretion results in delayed clearance of vincristine and vinblastine with a greater potential for toxicity [58,86,163,164].

The United States Prescribing Information for both vincristine and vinblastine recommends that the dose of either agent be reduced by 50 percent in patients with a serum bilirubin >3 mg/dL. Other guidelines for dosing adjustments have been recommended by some clinicians [58,109]:

●Serum bilirubin 1.5 to 3 mg/dL or aminotransferases two to three times ULN – Administer 50 percent of normal dose

●Serum bilirubin >3 mg/dL or aminotransferases >3 times ULN – Omit dose

There is less information available for vinorelbine. The United States Prescribing Information for vinorelbine recommends a 50 percent dose reduction for patients who develop moderate liver dysfunction during therapy (total bilirubin 2.1 to 3 mg/dL), and a 75 percent dose reduction for more severe hyperbilirubinemia (table 2). Others suggest that dose modification may not be necessary with mild to moderate liver impairment (total bilirubin <3 times ULN, transaminases <2.5 times ULN) [165,166].

Etoposide — Etoposide is not usually hepatotoxic at standard doses [167], although at least one report documents severe hepatocellular injury [168]. At high doses, etoposide has been associated with hyperbilirubinemia and elevated transaminases and alkaline phosphatase levels approximately three weeks after administration [169,170]. These abnormalities cleared without sequelae over 12 weeks.

Etoposide is extensively (97 percent) protein bound, and 70 to 80 percent of drug is eliminated through nonrenal mechanisms, presumably liver metabolism and bile excretion. Elevated serum bilirubin levels have been correlated with decreased clearance and enhanced leukopenia in some [171,172], but not all [173-175], studies. Others suggest that patients with increased bilirubin have an increased exposure to unbound drug, but without a reduction in total systemic clearance of the drug, possibly because of enhanced renal clearance [174,176,177].

Specific dosing guidelines for patients with hepatic insufficiency are not available in the United States Prescribing Information. Some clinicians recommend a 50 percent dose reduction for patients with a serum bilirubin 1.5 to 3 mg/dL or AST >3 times ULN [58,109], and reduction or omission of the dose for higher bilirubin levels.

Low albumin levels (<3.5 g/dL) are associated with an increase in the fraction of free drug, and this may lead to more pronounced hematologic toxicity [178,179]. A dose reduction by 33 or 50 percent has been recommended for patients with a reduced serum albumin [109,178].

Taxanes

Paclitaxel and docetaxel — In patients with normal baseline LFTs who are treated with either paclitaxel or docetaxel, transient elevations of alkaline phosphatase, AST, and bilirubin have been reported in approximately 5 to 20 percent of cases [180]. Hepatic toxicity is not dose dependent, and prolonged exposure to taxanes is not associated with cumulative hepatic toxicity.

Both paclitaxel and docetaxel undergo oxidation by the hepatic cytochrome P450 system and are excreted in the bile [181,182]. Clinically significant interactions have been reported with other drugs that are metabolized by cytochrome P450, including inhibitors and inducers of CYP3A4 (table 4) [183].

Patients with slightly elevated alkaline phosphatase or aminotransferases have decreased paclitaxel clearance and are at increased risk for severe treatment-related toxicity [184,185]. The impact of hepatic dysfunction on paclitaxel clearance varies depending upon the duration of drug infusion and the extent of liver abnormalities [186-188].

The United States Prescribing Information recommends the following dose modifications for preexisting liver disease in patients receiving three-hour infusions [189]:

●Total bilirubin ≤1.25 times ULN and AST <10 times ULN – total dose 175 mg/m²

●Total bilirubin 1.26 to 2 times ULN and aminotransferases <10 times ULN – total dose 135 mg/m²

●Total bilirubin 2.01 to 5 times ULN and aminotransferases <10 times ULN – total dose 90 mg/m²

●Total bilirubin >5 times ULN or aminotransferases ≥10 times ULN – not recommended

None of the data used to derive these guidelines were from patients treated with paclitaxel over one hour or with weekly therapy. It is unknown if these dose reduction schema are suitable for such patients, and further studies with a prospective design are needed.

For nabpaclitaxel (Abraxane), the United States Prescribing Information recommends reduced initial doses in patients with any malignancy who have severe hepatic impairment (AST >10 times ULN or bilirubin >5 times ULN); they also recommend not administering the drug to patients with pancreatic cancer who have moderate or severe hepatic impairment (ALT <10 times ULN and total bilirubin >1.5 times ULN, or ALT >10 times ULN).

Decreased docetaxel clearance occurs in patients with elevated bilirubin and/or transaminase levels. In some studies, even a slight or moderate increase in pretreatment bilirubin level was associated with toxic deaths [190-192].

Guidelines for dose reduction in the setting of hepatic dysfunction are variable:

●The United States Prescribing Information suggests that docetaxel not be given if the baseline serum bilirubin is above the ULN, or to patients with AST >1.5 times ULN in conjunction with an alkaline phosphatase >2.5 times ULN. Furthermore, because elevations in LFTs increase the risk of severe or life-threatening complications, LFTs should be obtained prior to each treatment cycle.

In the specific setting of gastric cancer when docetaxel is administered in conjunction with cisplatin and FU, a 20 percent dose reduction is recommended in patients who develop aminotransferase elevation >2.5 to ≤5 times ULN and alkaline phosphatase ≤2.5 times ULN, or aminotransferases >1.5 to ≤5 times ULN and alkaline phosphatase >2.5 to ≤5 times ULN [193]. For more severe hepatic dysfunction, drug discontinuation is recommended.

●Based upon pharmacokinetic modeling, others have recommended a 20 to 40 percent dose reduction for patients with grade 2 or 3 elevations in aminotransferases (>2.5 to 20 times ULN, (table 1)) at baseline in conjunction with elevated levels of alkaline phosphatase [194].

●A dose modification scheme for weekly docetaxel administration based upon preexisting liver dysfunction has been proposed for Asian patients [195].

Whether docetaxel is contraindicated in patients with severe liver dysfunction on the basis of metastatic cancer involvement is unclear. Administration of reduced-dose docetaxel has been successful in at least one report of a patient with breast cancer metastasis-related severe liver dysfunction [196].

Cabazitaxel — Cabazitaxel is a semisynthetic taxane that is approved for treatment of advanced prostate cancer. There is no published experience with cabazitaxel in patients with impaired hepatic function. However, cabazitaxel is extensively metabolized by the liver, and hepatic impairment is likely to increase exposure to the drug. The United States Prescribing Information suggests that the drug not be administered to patients with bilirubin levels more than 3 times ULN and that the starting dose be reduced in those with mild or moderate hepatic impairment (any bilirubin level above the ULN or AST >1.5 times ULN).

Ixabepilone — Ixabepilone is a microtubule inhibitor in the epothilone class that has been approved for treatment of chemotherapy resistant patients with metastatic breast cancer.

Ixabepilone is metabolized in the liver, and drug exposure is significantly increased in patients with hepatic disease [197]. The United States Prescribing Information for initial dose modification for ixabepilone monotherapy is indicated in the table (table 2). Subsequent dosing should be based upon treatment tolerance. Ixabepilone monotherapy is not recommended for aminotransferases >10 times ULN, or bilirubin >3 times ULN. The combination of ixabepilone with capecitabine is contraindicated in patients with aminotransferase elevation ≥2.5 times ULN or serum bilirubin above the ULN.

Eribulin — Eribulin mesylate, a synthetic analogue of halichondrin B, a substance derived from a marine sponge, inhibits the polymerization of tubulin and microtubules. Eribulin exposure is increased in patients with mild and moderate hepatic impairment [198]. Dose modification is recommended in the United States Prescribing Information:

●Child-Pugh A disease (table 5) – decrease in initial dose to 1.1 mg/m²

●Child-Pugh B disease – decrease initial dose to 0.7 mg/m²

●Child-Pugh C disease – do not administer

Miscellaneous agents

Bortezomib and other proteasome inhibitors — Bortezomib is predominantly metabolized by the liver, and exposure is increased in patients with moderate to severe liver impairment [199]. United States Prescribing Information suggests a reduced starting dose (0.7 mg/m²) in the first cycle for patients with a serum bilirubin >1.5 times ULN, with dose escalation or further dose reduction in subsequent cycles based upon patient tolerability. (See "Multiple myeloma: Administration considerations for common therapies", section on 'Proteasome inhibitors'.)

A reduced starting dose is also recommended for patients with moderate or severe hepatic impairment who are treated with the orally active proteasome inhibitor ixazomib. In addition, periodic monitoring of hepatic enzymes during therapy with both ixazomib and carfilzomib is recommended, given reports of drug-induced liver injury in <1 percent of treated patients.

Irinotecan and liposomal irinotecan — Combinations of irinotecan and FU are used in some patients with colorectal cancer prior to the resection of liver metastases. These regimens have been associated with both steatosis and hepatic vascular injury. (See "Potentially resectable colorectal cancer liver metastases: Integration of surgery and chemotherapy", section on 'Post-treatment assessment and duration of neoadjuvant therapy'.)

Nanoliposome-encapsulated irinotecan is approved in combination with FU plus leucovorin for treatment of gemcitabine-refractory metastatic pancreatic cancer. Transaminase elevations are reported in approximately 57 percent of patients but are severe in only 6 percent. (See "Initial systemic chemotherapy for metastatic exocrine pancreatic cancer".)

Irinotecan (whether liposome-encapsulated or not) is mainly eliminated by the liver and to a minor extent by the kidneys [200,201]. Two main metabolic pathways take place in the liver: conversion into inactive metabolites (via the CYP3A4 isoenzyme) and into the active metabolite SN-38 by carboxylesterase enzymes. Irinotecan clearance is diminished in patients with hepatic dysfunction, and exposure to the active metabolite SN-38 is increased relative to that in patients with normal hepatic function.

The tolerability of irinotecan in patients with hepatic dysfunction (serum bilirubin >2 mg/dL) has not been established. Specific dosing guidelines for patients with hepatic insufficiency are not available in the United States Prescribing Information for either unencapsulated irinotecan or liposomal irinotecan.

However, some clinicians recommend a reduction of the starting dose of unencapsulated irinotecan (eg, from 350 mg/m² to 200 mg/m² every three weeks) in patients with a pretreatment serum bilirubin level 1.5 to 3 times ULN to minimize the likelihood of diarrhea and neutropenia [109,201,202]. Dose reduction may also be needed for patients with a serum bilirubin 1 to 1.5 mg/dL, particularly with weekly administration schedules [203,204]. The United States Prescribing Information for liposomal irinotecan states only that "there is no recommended dose of the drug for patients with serum bilirubin above the upper limit of normal."

Patients with elevated aminotransferases do not appear to be more sensitive to irinotecan, and dose reduction is probably not needed [202]. However, the available data are insufficient to make a specific recommendation.

Platinum derivatives — Cisplatin is a rare cause of steatosis and cholestasis at standard doses [205]. Minor transient elevations in transaminases can occur during treatment [206] and are more frequent at higher doses [207]. Mild reversible increases in alkaline phosphatase and serum aminotransferases have also been reported with carboplatin and oxaliplatin. There is at least one report of carboplatin-induced liver failure [208] and one autopsy-documented case of hepatic SOS in a patient who received high-dose carboplatin and etoposide in addition to multiple other medications [209]. (See 'Hepatic vascular injury' above.)

Combinations of oxaliplatin and FU are used in some patients with colorectal cancer prior to the resection of liver metastases. These neoadjuvant regimens have been associated with hepatic vascular injury, and nodular regenerative hyperplasia (now termed idiopathic noncirrhotic portal hypertension [including nodular regenerative hyperplasia]). (See 'Hepatic vascular injury' above and "Noncirrhotic portal hypertension", section on 'Idiopathic noncirrhotic portal hypertension/Porto-sinusoidal vascular disease' and "Potentially resectable colorectal cancer liver metastases: Integration of surgery and chemotherapy", section on 'Post-treatment assessment and duration of neoadjuvant therapy'.)

All three drugs are predominantly renally excreted. No published studies are available to guide dosing in patients with liver dysfunction. Results from single case reports, clinical trials conducted in patients with metastatic colorectal cancer, and from a dose-escalating and pharmacologic study in patients with various tumor types indicate that oxaliplatin can be administered without dose modification, even in patients with severe liver dysfunction [210-212].

Asparaginase — Hepatotoxicity is frequent with Escherichia coli-derived L-asparaginase (L-asp). Hepatotoxicity is characterized by moderate reversible elevation of aminotransferases, bilirubin, and/or alkaline phosphatase. Hyperammonemia may develop as asparagine is broken down.

The mechanism is uncertain, but probably involves impaired protein synthesis from asparagine depletion. Liver steatosis, likely due to decreased lipoprotein synthesis, is found at autopsy in 42 to 87 percent of treated patients [213,214]. Some series describe a lower likelihood of abnormalities of LFTs following administration of pegylated-L-asp (Pegaspargase) [215], but others describe a high frequency of grade 3 or 4 transaminitis (63 percent) and hyperbilirubinemia (31 percent) [216]. Recovery may be prolonged.

Systemic clearance of L-asp is not dependent on renal or liver function. As a result, dose modifications are not usually required.

Procarbazine — Hepatotoxicity appears to be uncommon with procarbazine [217]. The drug has been implicated as a cause of granulomatous hepatitis [218].

Following oral administration, most procarbazine is rapidly converted to azo-procarbazine by erythrocyte and hepatic microsomal enzymes. Further metabolism has not been clearly defined. Although dose modification in patients with hepatic dysfunction is probably advisable, no formal guidelines have been published.

Lenalidomide and pomalidomide — Lenalidomide and pomalidomide are thalidomide analogs that are approved for treatment of multiple myeloma; pomalidomide is also approved for Kaposi sarcoma. (See "AIDS-related Kaposi sarcoma: Staging and treatment", section on 'Subsequent therapy' and "Multiple myeloma: Treatment of first or second relapse", section on 'Bortezomib, pomalidomide, dexamethasone (VPd)'.)

Potentially fatal hepatotoxicity is reported with both drugs, and LFTs should be monitored periodically during therapy.

Because pomalidomide is metabolized primarily by the liver, dose adjustment is recommended in the United States Prescribing Information for mild, moderate, or severe preexisting hepatic impairment. On the other hand, the elimination of lenalidomide is predominantly by the renal route, and the United States Prescribing Information does not specify the need for dose reduction in those with hepatic insufficiency.

Hydroxyurea — Hydroxyurea has been rarely reported to produce liver toxicity [219-221]. One case report describes hydroxyurea-induced hypersensitivity hepatitis with recurrence upon rechallenge [220].

Hydroxyurea is well absorbed from the gastrointestinal tract, and 50 percent of the drug is excreted unchanged in the urine. There are no published guidelines for dose reduction in patients with liver dysfunction.

Arsenic trioxide — On the basis of limited data from patients receiving arsenic trioxide for hepatocellular cancer, there appears to be no clear trend toward an increase in systemic exposure to the pharmacologically active metabolites of arsenic trioxide with decreasing levels of hepatic function [222]. Nevertheless, given the limited amount of available data, caution is advised in the use of the drug in patients with hepatic impairment, and patients with severe hepatic impairment (eg, Child-Pugh C cirrhosis (table 5)) should be closely monitored for toxicity.

Vorinostat and belinostat — Vorinostat is an inhibitor of histone deacetylase enzymes; it is used only for treatment of cutaneous T-cell lymphoma. (See "Treatment of advanced stage (IIB to IV) mycosis fungoides", section on 'Vorinostat'.)

Patients with varying degrees of hepatic dysfunction require dose reduction even though vorinostat pharmacokinetics are unaltered [223]. United States Prescribing Information for vorinostat recommends reduced doses for patients with mild to moderate hepatic impairment (total bilirubin >1 to 3 times ULN) and that the drug be avoided in those with severe impairment (total bilirubin >3 times ULN). Canadian guidelines recommend avoidance of the drug for all patients with total bilirubin ≥1.5 times ULN.

Belinostat is another histone deacetylase inhibitor that is approved for treatment of peripheral T-cell lymphoma. Belinostat can cause potentially fatal hepatotoxicity (there was one fatality from hepatic failure in 129 treated patients [224]). LFTs should be checked before treatment and before the start of each cycle; dose reduction is recommended for any grade 3 or worse toxicity (table 1).

Belinostat is metabolized in the liver, and hepatic impairment is likely to increase drug exposure. Patients with moderate to severe hepatic impairment were excluded from clinical trials, and there are insufficient data to recommend a belinostat dose in these patients.

Trabectedin — Trabectedin (ecteinascidin, ET-743), which is now synthesized, was originally isolated from the Caribbean sea sponge Ecteinascidia turbinata; it kills cells by poisoning the DNA nucleotide excision repair machinery and is an active agent for advanced STS. (See "Second and later lines of therapy for metastatic soft tissue sarcoma", section on 'Trabectedin (LMS)'.)

Severe hepatotoxicity, including hepatic failure, can occur in patients treated with trabectedin. In one trial, over 35 percent of patients had a grade 3 or 4 elevation in transaminases during therapy [225], despite pretreatment with high-dose dexamethasone. Dexamethasone is recommended prior to each dose of the drug and has been shown to mitigate severe hepatotoxicity with this agent [226].

LFTs should be assessed prior to each dose of trabectedin. The United States Prescribing Information includes recommended dose modifications for hepatotoxicity during therapy.

COMBINATION CHEMOTHERAPY REGIMENS — The majority of tumors are treated with combination rather than single-agent therapy; typically, the individual agents have different mechanisms of action and toxicity profiles. The potential for greater tumor cell kill is sometimes accompanied by greater toxicity, including hepatotoxicity.

For patients who develop hepatotoxicity while receiving a regimen with multiple drugs, it may not be immediately apparent which agent is responsible, and it is prudent to withhold all drugs until hepatotoxicity is reversed. If needed, dose adjustment for the next course should be undertaken for all drugs that might have been responsible for the hepatotoxicity, not just the most likely culprit.

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 5^th to 6^th 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 10^th to 12^th 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 agents, either alone or in combination with other drugs and radiation, may cause indirect or direct hepatotoxicity. Furthermore, abnormal liver function may alter drug metabolism and increase the risk of extrahepatic toxicity. (See 'Mechanisms' above.)

●Guidelines on dose modification for patients with preexisting hepatic disease are largely empiric. For some agents, including bendamustine, cytarabine, pemetrexed and pralatrexate, the vinca alkaloids, taxanes, procarbazine, bortezomib, ixazomib, carfilzomib, anthracyclines, vorinostat, ixabepilone, and trabectedin, there is agreement on the need for dose adjustment (or avoidance altogether) in patients with preexisting liver dysfunction in order to avoid excessive systemic toxicity (table 2). (See 'Dose reduction for patients with baseline hepatic impairment' above.)

There is less agreement on the need for dose reduction for other agents whose clearance is dependent upon liver metabolism, such as cyclophosphamide, ifosfamide, gemcitabine, cytarabine, dactinomycin, etoposide, irinotecan, methotrexate, procarbazine, and 6-mercaptopurine.

●Infection with hepatitis B (HBV) or hepatitis C (HCV) is a common disorder that can be exacerbated with cytotoxic chemotherapy. We agree with an updated year 2020 provisional clinical opinion from the American Society of Clinical Oncology, which endorses universal HBV screening for all patients beginning systemic anticancer therapy (cytotoxic chemotherapy, immunotherapy, molecularly targeted therapy) using three tests: hepatitis B surface antigen (HbSAg), hepatitis B core antibody (anti-HBc) total immunoglobulin (Ig) or IgG, and antibody to hepatitis B surface antigen (anti-HBs). 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). (See 'HBV screening and management' above.)

Clinicians should also consider testing for chronic hepatitis C virus 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 LFTs, and if there is no dramatic change, continued chemotherapy treatment without dose modification is appropriate. (See 'Hepatitis C' above.)