ABSTRACT: Advanced cancer in the setting of liver dysfunction poses a dilemma for physicians, as many cancer chemotherapeutic agents undergo hepatic metabolism. Most cytotoxic drugs have a narrow therapeutic index, and the administration of chemotherapy to patients with liver impairment results in complicated safety issues. We present a concise review of cancer chemotherapy dosing in the setting of liver dysfunction. Although caution in treating all patients with hepatic failure is essential, the use of certain agents provokes greater concern than others. Continuous-infusion fluorouracil(Drug information on fluorouracil), capecitabine(Drug information on capecitabine) (Xeloda), mechlorethamine (Mustargen), cyclophosphamide(Drug information on cyclophosphamide), topotecan(Drug information on topotecan) (Hycamtin), and oxaliplatin(Drug information on oxaliplatin) (Eloxatin) appear to be relatively well tolerated. On the contrary, taxanes, vinca alkaloids, irinotecan(Drug information on irinotecan) (Camptosar), and anthracyclines may cause unacceptable toxicity if administered to patients with poor hepatic function. For many anticancer agents, the paucity of data prohibits formal dosing recommendations, and most guidelines remain empiric.
The administration of chemotherapy to cancer patients with hepatic dysfunction requires careful consideration. There are a variety of ways in which liver impairment affects drug kinetics, including changing the intrinsic hepatic clearance of drugs, reducing hepatic metabolic capacity, and altering the biliary excretion of drugs. In addition, low serum albumin levels lead to increased fractions of free drug, and portal hypertension can affect drug absorption.
Unfortunately, most clinical trials exclude patients with impaired hepatic function; much of what is known about individual chemotherapeutic agents in the setting of liver failure is based on small, retrospective studies. Very few agents have undergone formal phase I testing in liver dysfunction cohorts, and empirical guidelines are frequently used in clinical practice. Furthermore, there is no standardized system with which to define liver dysfunction in patients with cancer. The serum total bilirubin level is the marker most commonly used to assess the need for chemotherapy dose adjustments, but this represents an oversimplified strategy. To further complicate issues, various sources often differ in dosing recommendations, with no consensus. Thus, there are many potential hazards involving the administration of cancer chemotherapy to patients with impaired hepatic function.
Two review articles published in 1992 by Perry and Koren et al and a subsequent article in 1998 by Donelli et al have provided important guidelines for the use of chemotherapywith liver dysfunction. Since 1998, there have been a number of important new findings, particularly regarding irinotecan (Camptosar), fluorouracil (5-FU), capecitabine (Xeloda), gemcitabine(Drug information on gemcitabine) (Gemzar), paclitaxel(Drug information on paclitaxel), and oxaliplatin (Eloxatin) in patients with impaired hepatic function. Patients with gastrointestinal malignancies may benefit from these agents; however, the high incidence of hepatic metastases, often accompanied by liver function test abnormalities, precludes their use. We have compiled the results of these newest findings and have highlighted pertinent recommendations from past reviews.
Hepatic metabolism is the major route of elimination of 5-FU. Dihydropyrimidine dehydrogenase (DPD) is the initial, rate-limiting enzyme in 5-FU catabolism. In addition to being present in the liver, DPD is also found in the gastrointestinal tract and in tissues throughout the body. Early reports described significant toxicity when full-dose bolus 5-FU was administered to patients with liver metastases and jaundice, leading to the recommendation that 5-FU be withheld in patients with serum bilirubin concentrations greater than 5 mg/dL.
A phase I study evaluated infusional 5-FU in cancer patients with organ dysfunction. A total of 64 patients were divided into three cohorts. The first cohort had renal insufficiency (serum creatinine: 1.5-3.0 mg/dL) but normal total bilirubin levels. The second cohort had normal renal function but mild-to-moderate hepatic dysfunction with total bilirubin levels of 1.5 to 5.0 mg/dL. The third cohort had normal renal function and moderate-tosevere hepatic dysfunction with total bilirubin levels greater than 5.0 mg/dL. In all cohorts, patients were safely treated with 5-FU (2,600 mg/m2) administered as a continuous intravenous infusion over 24 hours along with leucovorin (500 mg/m2) on a weekly schedule. There was no relationship between serum bilirubin and 5-FU clearance, and toxicity did not appear to correspond to organ dysfunction.
Capecitabine is an oral prodrug that is metabolized to 5-FU and has clinical activity that mimics infusional 5-FU. Capecitabine is readily absorbed from the gastrointestinal tract and activated, through a series of enzymatic reactions occurring first in the liver and subsequently in most tissues (including tumor tissue), to the active drug 5-FU. It is catabolized by DPD as described above.
A study of 14 patients with normal liver function and 13 patients with liver function test abnormalities due to liver metastases demonstrated no clinically significant influence on the pharmacokinetic parameters of capecitabine or its metabolites in the setting of hepatic dysfunction (mean bilirubin: 6.5 mg/dL, range: 0.9-28.3 mg/dL).
In a separate report, a woman with metastatic breast cancer and severe liver dysfunction (total bilirubin: 12 mg/dL) achieved a partial response after seven cycles of capecitabine at 2,500 mg/m2/d in two divided doses for 2 weeks followed by 1 week of rest. The treatment was well tolerated, with National Cancer Institute Common Toxicity Criteria (NCI-CTC) grade 2 hand-foot syndrome and mild nausea being the only side effects. Based on these reports, capecitabine can be considered for patients with liver dysfunction.
Gemcitabine (Gemzar) is inactivated by cytidine deaminase to an inactive metabolite, which is primarily eliminated in the kidney. A phase I study of gemcitabine found that patients with serum aspartate aminotransferase (AST) elevation greater than two times normal, but with normal bilirubin levels, tolerated gemcitabine well without a need for dose reduction. In contrast, patients with elevated total bilirubin levels (median: 2.7 mg/dL, range: 1.7-5.7 mg/dL) had a significant deterioration in liver function with the administration of gemcitabine.
Of 8 patients, 3 developed doselimiting toxicity (DLT) at a dose of 800 mg/m2; 8 of 10 developed DLT at a dose of 950 mg/m2. Further hyperbilirubinemia and elevated transaminases were the most common DLTs. The deterioration in liver function was transient, often lasting less than 1 week. There were no apparent pharmacokinetic differences compared with historical controls. The authors concluded that patients with elevated bilirubin levels should initially be treated with a weekly gemcitabine dose of 800 mg/m2, and subsequently escalated doses if the therapy is tolerated.
Irinotecan (Camptosar) is mainly eliminated by the liver and, to a lesser extent, by the kidneys. Irinotecan's active metabolite, SN-38, is glucuronidated by the hepatic enzymes uridine diphosphate glucuronosyltransferases. Severe neutropenia and diarrhea have been reported in patients with Gilbert's disease. Certain genetic variants in the UDP-glucuronosyltransferase 1A1 (UGT1A1) gene predict the risk of severe neutropenia from irinotecan.
A phase I study has been conducted administering irinotecan on an every- 3-week schedule to patients with varying degrees of liver dysfunction.[ 11] High bilirubin and alkaline phosphatase levels were associated with an exponential decrease in the clearance of irinotecan, and drug toxicity correlated with serum bilirubin concentration. Patients with total bilirubin levels less than 1.5 times the upper limit of normal (ULN) tolerated full-dose therapy (350 mg/m2 every 3 weeks). The maximum tolerated dose for patients with total bilirubin levels 1.5 to 3.0 times the ULN was 200 mg/m2 every 3 weeks. One of five patients developed DLT at this dose. Three of six patients with bilirubin levels 1.5 to 3.0 times the ULN developed DLT at a dose of 240 mg/m2. Three patients with bilirubin levels greater than three times the ULN (range: 3.6- 5.8 times the ULN) were treated with one cycle of irinotecan at a dose of 100 mg/m2. Although none of the three patients developed DLT, most experienced rapid hepatic tumor progression associated with aggravation of liver dysfunction and worsening of performance status. Therefore, no dosing recommendations could be made for patients with serum bilirubin levels greater than three times the ULN. The most common DLTs in patients with hyperbilirubinemia were NCICTC grade 4 febrile neutropenia and diarrhea.
A separate phase I study confirmed that irinotecan dose reductions are required in patients with liver impairment.[ 12] Twelve patients with hyperbilirubinemia (median serum bilirubin: 2.1 mg/dL, range: 1.0-5.5 mg/dL) weregiven irinotecan on an every-3-week schedule. Three of five patients developed DLT at a dose of 145 mg/m2, and zero of seven patients developed DLT at a dose of 115 mg/m2. Two of the DLTs were neutropenia and one was worsening liver function. There were no episodes of dose-limiting diarrhea in patients with an increased bilirubin level. This is consistent with the hypothesis that biliary excretion of SN-38 is responsible for the diarrhea. The authors conclude that patients with elevated bilirubin treated with irinotecan have an increased risk of toxicity; a dose reduction is recommended.
Topotecan (Hycamtin) pharmacokinetics exhibit significant interpatient variation. It is metabolized via pH-dependent hydrolysis of its lactone moiety, with minor metabolic pathways involving glucuronidation and the hepatic enzyme CYP3A. Topotecan has been studied in patients with impaired hepatic function. Twentyone patients were enrolled: 7 control patients with normal hepatic function (serum bilirubin: < 1.2 mg/dL) and 14 patients with liver dysfunction (mean serum bilirubin: 4.3 mg/dL, range: 1.7-14.9 mg/dL). Patients were treated with intravenous topotecan at doses of 0.5, 1.0, or 1.5 mg/m2 daily for 5 consecutive days. Most patients received more than one course of treatment.
No pharmacokinetic or pharmacodynamic alterations were found in patients with impaired liver function when compared with the control group. In addition, the nature and severity of treatment-induced toxic effects were similar in patients with and without liver injury. Patients with impaired hepatic function tolerated topotecan doses of 1.5 mg/m2 administered daily for 5 days without evidence of dose-limiting toxicity. For this reason, topotecan dose adjustments are not required for patients with liver dysfunction.