Division of Hematology - Oncology

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, capecitabine (Xeloda), mechlorethamine (Mustargen), cyclophosphamide, topotecan (Hycamtin), and oxaliplatin (Eloxatin) appear to be relatively well tolerated. On the contrary, taxanes, vinca alkaloids, 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. MARY F. MULCAHY, MD Assistant Professor Department of Medicine Division of Hematology-Oncology Robert H. Lurie Comprehensive Cancer Center of Northwestern University Chicago, Illinois T he 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 cantherapy with liver dysfunction. Since 1998, there have been a number of important new findings, particularly regarding irinotecan (Camptosar), fluorouracil (5-FU), capecitabine (Xeloda), gemcitabine (Gemzar), paclitaxel, and oxaliplatin (Eloxatin) in patients with impaired hepatic function. Patients with gastrointestinal malignancies may benefit from these agents; however, the high incidence of he patic 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. cer. 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[l] and Koren et al[2] and a subsequent article in 1998 by Donelli et al[3] have provided important guidelines for the use of chemoFinancial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this