JOHN W. EKLUND, MD

Hematology/Oncology FellowDepartment of MedicineDivision of Hematology-OncologyRobert H. LurieComprehensive Cancer Center ofNorthwestern University

STEVE TRIFlLIO, RPh

Clinical PharmacistNorthwestern Memorial Hospital

ABSTRACT

Advanced cancer in the setting of liver dysfunction poses a dilemmafor physicians, as many cancer chemotherapeutic agents undergo he-patic metabolism. Most cytotoxic drugs have a narrow therapeutic in-dex, and the administration of chemotherapy to patients with liver im-pairment results in complicated safety issues. We present a concise re-view of cancer chemotherapy dosing in the setting of liver dysfunction.Although caution in treating all patients with hepatic failure is essen-tial, the use of certain agents provokes greater concern than others.Continuous-infusion fluorouracil, capecitabine (Xeloda), mechlor-ethamine (Mustargen), cyclophosphamide, topotecan (Hycamtin), andoxaliplatin (Eloxatin) appear to be relatively well tolerated. On thecontrary, taxanes, vinca alkaloids, irinotecan (Camptosar), andanthracyclines may cause unacceptable toxicity if administered to pa-tients with poor hepatic function. For many anticancer agents, the pau-city of data prohibits formal dosing recommendations, and most guide-lines remain empiric.

MARY F. MULCAHY, MD

Assistant ProfessorDepartment of MedicineDivision of Hematology-OncologyRobert H. LurieComprehensive Cancer Center ofNorthwestern UniversityChicago, Illinois

T he administration of chemo-therapy to cancer patients with

hepatic dysfunction requirescareful consideration. There are a va-riety of ways in which liver impair-ment affects drug kinetics, includingchanging the intrinsic hepatic clear-ance of drugs, reducing hepatic meta-bolic capacity, and altering the biliaryexcretion of drugs. In addition, lowserum albumin levels lead to increasedfractions of free drug, and portal hy-pertension can affect drug absorption.

Unfortunately, most clinical trialsexclude patients with impaired hepat-ic function; much of what is knownabout individual chemotherapeuticagents in the setting of liver failure isbased on small, retrospective studies.Very few agents have undergone for-mal phase I testing in liver dysfunc-tion cohorts, and empirical guidelinesare frequently used in clinical prac-tice. Furthermore, there is no stand-ardized system with which to defineliver dysfunction in patients with can-

therapy with liver dysfunction. Since1998, there have been a number ofimportant new findings, particularlyregarding irinotecan (Camptosar), flu-orouracil (5-FU), capecitabine (Xelo-da), gemcitabine (Gemzar), paclitaxel,and oxaliplatin (Eloxatin) in patientswith impaired hepatic function. Pa-tients with gastrointestinal malignan-cies may benefit from these agents;however, the high incidence of he pat-ic metastases, often accompanied byliver function test abnormalities, pre-cludes their use. We have compiledthe results of these newest findingsand have highlighted pertinent rec-ommendations from past reviews.

cer. The serum total bilirubin level isthe marker most commonly used toassess the need for chemotherapy doseadjustments, but this represents anoversimplified strategy. To furthercomplicate issues, various sources of-ten differ in dosing recommendations,with no consensus. Thus, there aremany potential hazards involving theadministration of cancer chemothera-py to patients with impaired hepaticfunction.

Two review articles published in1992 by Perry[l] and Koren et al[2]and a subsequent article in 1998 byDonelli et al[3] have provided impor-tant guidelines for the use of chemo-

Financial Disclosure: The authors have nosignificant financial interest or other relation-ship with the manufacturers of any productsor providers of any service mentioned in thisarticle.

1057JULY 2005 . ONCOLOGY

lrinotecanFluoropyrimidines

Hepatic metabolism is the majorroute of elimination of 5-FU. Dihy-dropyrimidine dehydrogenase (DPD)is the initial, rate-limiting enzyme in5-FU catabolism. In addition to beingpresent in the liver, DPD is also foundin the gastrointestinal tract and in tis-sues throughout the body. Early re-ports described significant toxicitywhen full-dose bolus 5-FU was ad-ministered to patients with liver me-tastases and jaundice, leading to therecommendation that 5-FU be with-held in patients with serum bilirubinconcentrations greater than 5 mg/dL. [4]

A phase I study evaluated infusion-al 5-FU in cancer patients with organdysfunction. [5] A total of 64 patientswere divided into three cohorts. Theflfst cohort had renal insufficiency (se-rum creatinine: 1.5-3.0 mg/dL) butnormal total bilirubin levels. The sec-ond cohort had normal renal functionbut mild-to-moderate hepatic dysfunc-tion with total bilirubin levels of 1.5to 5.0mg/dL. The third cohort had nor-mal renal function and moderate-to-severe hepatic dysfunction with totalbilirubin levels greater than 5.0 mg/dL.In all cohorts, patients were safelytreated with 5-FU (2,600 mg/m2) ad-ministered as a continuous intravenousinfusion over 24 hours along with leu- icovorin (500 mg/m2) on a weeklyschedule. There was no relationshipbetween serum bilirubin and 5-FUclearance, and toxicity did not appearto correspond to organ dysfunction.

Capecitabine is an oral prodrug thatis metabolized to 5-FU and has clini-cal activity that mimics infusional5-FU. Capecitabine is readily ab-sorbed from the gastrointestinal tractand activated, through a series of en-zymatic reactions occurring flfSt inthe liver and subsequently in mosttissues (including tumor tissue), to theactive drug 5-FU. It is catabolized byDPD as described above.

One or two copies of this article for per-sonal or internal use may be made at no charge.Copies beyond that number require that a 9~per page per copy fee be paid to the CopyrightClearance Center, 222 Rosewood Drive, Dan-vers, MA 01970. Specify ISSN 0890-9091. Forfurther information, contact the CCC at 508-750-8400. Write publisher for bulk quantities.

Irinotecan (Camptosar) is mainlyeliminated by the liver and, to a lesserextent, by the kidneys. Irinotecan'sactive metabolite, SN-38, is glucu-ronidated by the hepatic enzymesuridine diphosphate glucuronosyl-transferases. Severe neutropenia anddiarrhea have been reported in patientswith Gilbert's disease.[9] Certain ge-netic variants in the UDP-glucurono-syltransferase 1A1 (UGT1A1) genepredict the risk of severe neutropeniafrom irinotecan.[10]

A phase I study has been conduct-ed administering irinotecan on an ev-ery-3-week schedule to patients withvarying degrees of liver dysfunc-tion.[ll] High bilirubin and alkalinephosphatase levels were associatedwith an exponential decrease in theclearance of irinotecan, and drug tox-icity correlated with serum bilirubinconcentration. Patients with total bi.,lirubin levels less than 1.5 times theupper limit of normal (ULN) tolerat-ed full-dose therapy (350 mg/m2 ev-ery 3 weeks). The maximum tolerateddose for patients with total bilirubinlevels 1.5 to 3.0 times the ULN was200 mg/m2 every 3 weeks. One of fivepatients developed DL T at this dose.Three of six patients with bilirubin lev-els 1.5 to 3.0 times the ULN developedDL T at a dose of 240 mg/m2. Threepatients with bilirubin levels greaterthan three times the ULN (range: 3.6-5.8 times the ULN) were treated withone cycle of irinotecan at a dose of100 mg/m2. Although none of the threepatients developed DLT, most expe-rienced rapid hepatic tumor progres-sion associated with aggravation ofliver dysfunction and worsening ofperformance status. Therefore, no dos-ing recommendations could be madefor patients with serum bilirubin lev-els greater than three times the ULN.The most common DL Ts in patientswith hyperbilirubinemia were NCI-CTC grade 4 febrile neutropenia anddiarrhea.

A separate phase I study confIrmedthat irinotecan dose reductions are re-quired in patients with liver impair-ment.[12] Twelve patients with hyper-bilirubinemia (median serum bilirubin:2.1 mg/dL, range: 1.0-5.5 mg/dL) were

1058 ONCOLOGY' VOLUME 19 . NUMBER

A study of 14 patients with noffilalliver function and 13 patients with liverfunction test abnoffilalities due to livermetastases demonstrated no clinicallysignificant influence on the pharma-cokinetic parameters of capecitabineor its metabolites in the setting of he-patic dysfunction (mean bilirubin:6.5 mgidL, range: 0.9-28.3 mgidL).[6]

In a separate report, a woman withmetastatic breast cancer and severeliver dysfunction (total bilirubin:12 mgidL) achieved a partial responseafter seven cycles of capecitabine at2,500 mg/m2/d in two divided dosesfor 2 weeks followed by 1 week ofrest.[7] The treatment was well toler-ated, with National Cancer InstituteCommon Toxicity Criteria (NCI -CTC)grade 2 hand-foot syndrome and mildnausea being the only side effects.Based on these reports, capecitabinecan be considered for patients with liv-er dysfunction.

Gemcitabine

Gemcitabine (Gemzar) is inactivat-ed by cytidine deaminase to an inac-tive metabolite, which is primarilyeliminated in the kidney. A phase Istudy of gemcitabine found that pa-tients with serum aspartate amino-transferase (AST) elevation greaterthan two times normal, but with nor-mal bilirubin levels, tolerated gemcit-abine well without a need for dosereduction.[8] In contrast, patients withelevated total bilirubin levels (median:2.7 mg/dL, range: 1.7-5.7 mg/dL) hada significant deterioration in liverfunction with the administration of

~ gemcitabine.I Of 8 patients, 3 developed dose-

limiting toxicity (DLT) at a dose of800 mg/m2; 8 of 10 developed DLT ata dose of 950 mg/m2. Further hyper-bilirubinemia and elevated transami-nases were the most common DLTs.The deterioration in liver function wastransient, often lasting less than1 week. There were no apparent phar-macokinetic differences comparedwith historical controls. The authorsconcluded that patients with elevatedbilirubin levels should initially be treat-ed with a weekly gemcitabine dose of800 mg/m2, and subsequently escalat-ed doses if the therapy is tolerated.

given irinotecan on an every-3-weekschedule. Three of five patients de-veloped DLT at a dose of 145 mg/m2,and zero of seven patients developedDL T at a dose of 115 mg/m2. Two ofthe DLTs were neutropenia and onewas worsening liver function. Therewere no episodes of dose-limiting diar-rhea in patients with an increased bi-lirubin level. This is consistent with thehypothesis that biliary excretion ofSN-38 is responsible for the diarrhea.The authors conclude that patients withelevated bilirubin treated with irinote-can have an increased risk of toxicity; adose reduction is recommended.

leading to poor accrual. Only one pa-tient in the first cohort was treatedwith a 3-hour infusion, so no conclu-sion can be drawn for these patientswith elevated AST and normal biliru-bin. For patients in the second cohort,doses up to 100 mg/m2 over 3 hoursdemonstrated safety with no DLTs.Two patients were treated at a dose of125 mg/m2, with one experiencingDLT, prior to study closure. Six pa-tients in the third cohort were treated

Topotecan

Topotecan (Hycamtin) pharma-cokinetics exhibit significant interpa-tient variation. It is metabolized viapH-dependent hydrolysis of its lactonemoiety, with minor metabolic pathwaysinvolving glucuronidation and thehepatic enzyme CYP3A. Topotecanhas been studied in patients with im-paired hepatic function.[13] Twenty-one patients were enrolled: 7 controlpatients with normal hepatic function(serum bilirubin: < 1.2 mg/dL) and14 patients with liver dysfunction(mean serum bilirubin: 4.3 mg/dL,range: 1.7-14.9 mg/dL). Patients weretreated with intravenous topotecan atdoses of 0.5, 1.0, or 1.5 mg/m2 dailyfor 5 consecutive days. Most patientsreceived more than one course oftreatment.

No pharmacokinetic or pharmaco-dynamic alterations were found inpatients with impaired liver functionwhen compared with the controlgroup. In addition, the nature and se-verity of treatment-induced toxic ef-fects were similar in patients with andwithout liver injury. Patients withimpaired hepatic function tolerated to-potecan doses of 1.5 mg/m2 adminis-tered daily for 5 days without evidenceof dose-limiting toxicity. For this rea-son, topotecan dose adjustments arenot required for patients with liver

dysfunction.

cretion. A 96-hour infusion of pacli-taxel was evaluated for patients withliver metastases and total bilirubin lev-els up to 2.0 mg/dL.[14] Metastaticliver disease was strongly correlatedwith reduced drug clearance, highersteady-state concentrations, and in-creased hematologic toxicity. Arecommendation was made to dose-reduce paclitaxel by 25% in patientswith extensive liver metastases (ex-tensive defined as masses greater than2 cm or diffuse involvement).

A phase I trial of paclitaxel in 81patients evaluated three cohorts withvarying degrees of liver dysfunc-tion.[15] The first cohort had AST ele-vations at least two times the ULN andbilirubin levels less than 1.5 mg/dL.The second cohort had bilirubin levelsbetween 1.6 and 3.0 mg/dL with anyAST level. The third cohort had biliru-bin levels greater than 3.0 mg/dL withany AST level. Although the trial wasinitially designed to assess a 24-hourinfusion schedule, it was extended toinclude a 3-hour regimen. Sixty pa-tients were treated with the 24-hourinfusion schedule and 21 patients withthe 3-hour infusion schedule.

Patients in the fIrst cohort weretreated at a dose of 200 mg/m2 over24 hours. Five of seven patients expe-rienced DL T, and it was clear that adose de-escalation, rather than theplanned dose escalation, would benecessary. The dose was decreased insubsequent groups of patients. Exces-sive DLT was experienced until thedose of 50 mg/m2 was reached. Noneof the three patients treated at a doseof 50 mg/m2 had a DLT. In the sec-ond cohort, the 24-hour infusion at adose of 75 mg/m2 caused DLT in twoof six patients. In the third cohort,two of three patients had DLT at thisdose and none of six at a dose of50 mg/m2. For a 24-hour infusion ofpaclitaxel, doses greater than 50 to75 mg/m2 are not tolerated for patientswith liver dysfunction. The most fre-quent DL T was myelosuppression, butneurotoxicity, mucositis, and asthe-nia were also seen.

The administration of paclitaxelover 3 hours in the setting of liverdysfunction is less clear. The studywas closed prematurely due to thecommercial availability of paclitaxel

Taxanes

Taxanes are mainly metabolizedby the liver, and undergo biliary ex-

1059JULY 2005 . ONCOLOGY

Reference Guide

Therapeutic AgentsMentioned in This Article

Capecitabine (Xeloda)

Carboplatin

Cisplatin

Cyclophosphamide

Docetaxel (Taxotere)

Doxorubicin

Epirubicin (Ellence)

Etoposide

Fluorouracil (5-FU)

Gemcitabine (Gemzar)

Irinotecan (Camptosar)

leucovorin

Mechlorethamine (Mustargen)

Methylprednisolone

Oxaliplatin (Eloxatin)

Paclitaxel

Prednisone

Rituximab (Rituxan)

Topotecan (Hycamtin)

Vinblastine

Vincristine

Vinorelbine

Brand names are listed in parentheses only if adrug is not available generically and is marketedas no more than two trademarked or registeredproducts. More familiar alternative genericdesignations may also be included parenthetically.

adjustments in patients with hepaticdysfunction. There are no fonnal stud-ies evaluating the dosing of theseagents in patients with liver failure. Ina pilot study of 11 patients with liverdysfunction (bilirubin> 1.5 times theULN) due to metastatic breast cancer,10 patients showed improvement inliver function and 7 patients had apartial response after treatment withcisplatin and vinorelbine.[21] The pa-tients received up to six cycles of cis-platin at a dose of 75 mg/m2 every 21days and vinorelbine at 20 mg/m2 ondays 1 and 8 of a 21-day cycle. Onepatient died from an intracerebral hem-orrhage that was possibly related totreatment. Myelosuppression was themost frequently reported adverse event.Other adverse events included nausea,vomiting, and mild neurotoxicity.

- pretreatment total bilirubin level was

12.0 mg/dL. Intravenous docetaxelwas initiated at a dose of 20 mgim2/wk.Due to myelosuppression after the fIrstfew cycles, the dosing schedulechanged and docetaxel was adminis-tered whenever hematologic recov-ery (absolute neutrophil count [ANC]greater than 1,500 and platelet countgreater than 75,000) occurred (range:7-21 days). The patient had a sus-tained objective response to treatment.The major toxicity was a single epi-sode of NCI-CTC grade 3 febrile neu-tropenia. While docetaxel may be used

. with caution in selected patients withhepatic dysfunction, further studiesare required to determine the appro-priate dose adjustments for patientswith liver impairment.

Table 1

Chemotherapeutic Agents forWhich Dose Adjustment forMild-to-Moderate LiverDysfunction Is Not Needed

. Capecitabine[6]

. Carboplatin[3]. Cisplatin[3]. Cyclophosphamide[33]

. Fluorouracil[5]

. Mechlorethamine[34]. Oxaliplatin[20]. Topotecan[13]Platinum Agents

Anthracyclinesat a dose of 50 mg/m2 with one DL T,and six patients were treated at a doseof75 mg/m2 with three patients expe-riencing DLTs. For moderate liverdysfunction (bilirubin: 1.6-3.0 mg/dL)3-hour paclitaxel infusion can be giv-en safely at a dose of 100 mg/m2,while patients with severe liver dys-function (bilirubin: > 3.0 mg/dL) willlikely tolerate 50 mg/m2.

Docetaxel (Taxotere) also requiresdose adjustment for patients with liv-er impairment. Patients with liver im-pairment treated with docetaxel havedemonstrated an increased risk of neu-tropenia and mucositis,[16] and treat-ment-related death.[17] There is aboxed warning in the docetaxel pre-scribing information stating that thedrug should generally not be given topatients with bilirubin levels greaterthan the ULN, or to patients with ASTand/or alanine aminotransferase(ALT) levels greater than 1.5 timesthe ULN concomitant with alkalinephosphatase levels greater than 2.5times the ULN.[18]

Despite this, a case of successfuldocetaxel therapy in a woman withsevere obstructive jaundice second-ary to metastatic breast cancer hasbeen reported.[19] The patient's

The third-generation platinum ox-aliplatin undergoes rapid biotransfor-mation in the blood. It does notundergo cytochrome P450-mediatedmetabolism and is not associated withany hepatic enzyme- or protein-bind-ing-based drug interactions. A phase Itrial has been conducted in patients withnonnal, mild, moderate, and severe liverdysfunction (severe liver dysfunctionwas defined as a serum total bilirubinlevel greater than 3.0 mg/dL).[20]

Investigators found that oxaliplatinadministered at the standard dose of130 mg/m2 every 21 days was welltolerated in patients with all levels ofhepatic failure, and that liver dysfunc-tion caused no apparent alteration inthe clearance of platinum species fromthe plasma. There were no dose-lim-iting events at the maximum dose leveltested. Unfortunately, they did not re-port the median or range for totalbilirubin level in the severe liver dys-function group. In addition, only threepatients in the severe liver dysfunc-tion group received the l30-mg/m2dose. Although it is likely that oxali-platin is safe in patients with mild-to-moderate liver dysfunction, it remainsunclear if full-dose oxaliplatin is safein patients with markedly elevated se-rum bilirubin levels.

Cisplatin and carboplatin are pri-marily excreted by the kidney, andare therefore unlikely to require dose

Address all correspondence to:Mary F. Mulcahy, MD676 North St. Clair, Suite 850Chicago, n.. 60611e-mail: m-mulcahy@northwestem.edu

1060 ONCOLOGY' VOLUME 19 . NUMBER 8

The anthracyclines are primarilymetabolized and excreted by the liv-er. Doxorubicin is the anthracyclinethat has been studied most extensive-ly in patients with poor liver function.The main toxicity of doxorubicin inthe setting of liver dysfunction ismyelosupression. Other doxorubicin-induced toxicities are dependent onthe peak concentration rather than thetarget drug concentration (area underthe concentration-time curve [AUC]).Prolonged infusion schedules may re-duce the risk of nonhematologic

toxicity.[22,23]In a study by Benjamin et al, se-

vere toxicity (pancytopenia, mucosi-tis, and three drug-related deaths) wasdocumented in eight patients with he-patic impairment treated with full-dosedoxorubicin.[24] An additional ninepatients were treated with a dose-ad-justment scheme based largely on theserum bilirubin concentration. Hema-tologic nadirs in these nine patientswere similar to those of control pa-tients, and no mucositis or drug-relat-ed deaths occurred. Based on theseresults, the investigators recommend(1) a 50% dose reduction of doxoru-bicin if the total bilirubin level is 2.0to 3.0 mg/dL or if the serum transam-inases are greater than three times theULN, (2) a 75% dose reduction fortotal bilirubin levels between 3.0 and

Table 2

Recommended Dose Adjustment for Liver Dysfunction

Drug Liver Dysfunction Dose

Docetaxel[18] Bilirubin> ULN or OmitAST/ALT> 1.5 x ULN andalkaline phosphatase> 2.5 x ULN

Doxorubicin[24] Bilirubin 2.0-3.0 mg/dL Reduce by 50%Bilirubin 3.1-5.0 mg/dL Reduce by 75%Bilirubin> 5.0 mg/dL Omit

Epirubicin[27] Abnormal AST Adjustment required

Gemcitabine[8] Mild to moderate 800 mg/m2,increase as tolerated

200 mg/m2 every 3 wk115 mg/m2 every 3 wk

5.0 mg/dL, and (3) withholdingdoxorubicin if the total bilirubin isgreater than 5.0 mg/dL. In contrast,Donelli et al[3] contend that indis-criminate dose reductions are notwarranted, and recommend dose ad-justments only for serum total biliru-bin greater than 3.0 mg/dL.

Unlike doxorubicin where doseadjustments are based on total biliru-bin levels, epirubicin (Ellence) clear-ance has been shown to correlate withserum AST .[25,26] An elegant studyby Dobbs et al evaluated an epirubi-cin dose-modification algorithm inbreast cancer patients with liver im-pairment.[27] They identified the tar-get plasma exposure to epirubicin thatwould be expected with standard dos-ing for patients with normal liver func-tion. An epirubicin dosage schemewas designed, based on serum AST,that would achieve that target plasmalevel. A simple nomogram from whichdoses can be selected based on ASTwas devised and subsequently vali-dated in 40 patients with liver dys-function. Dobbs et al found thatepirubicin dosing based on AST issafe and may reduce pharmacokinet-ic variability. These results are pre-liminary and further studies arewarranted prior to the general accep-tance of this nomogram.

Irinotecan[11,12]

Paclitaxel[15]

Vinblastine or

vincristine[1,29]

100 mg/m2 over 3 h50 mg/m2 over 3 hReduction required

Reduce by 50%OmitConsider reduction

Bilirubin 1.5-3.0 x ULNBilirubin median 2.1 mgidL(range: 1.0-5.5 mgidL)

Bilirubin 1.6-3.0 mg/dLBilirubin> 3.0 mgidLIncreased AST

Bilirubin 1.5-3.0 mg/dLBilirubin> 3.0 mgidLNormal bilirubin,increased alkaline phosphatase

Bilirubin 2.1-3.0 mg/dLBilirubin> 3.0 mgidL> 75% liver metastases

Bilirubin 1.5-3.0 mgidLBilirubin> 3.0 mgidLLow albumin

Vinorelbine[30,31 ]

Etoposide[1.32]

Reduce by 50%Reduce by 75%Reduce by 50%

Reduce by 50%OmitConsider reduction

ALT = serum alanine aminotransferase; AST = serum aspartate aminotransferase;ULN = upper limit of normal.

Vinca Alkaloids

ing in a greater degree of hematologictoxicity. [32] It is excreted primarilyin the bile. The decreased metabolicclearance in the setting of liver dys-function can be compensated for by anincrease in renal clearance. Patients withelevated bilirubin with preserved renalfunction and albumin levels may toler-ate full doses of etoposide. Dose reduc-tion is recommended for patients withhypoalbuminemia regardless of biliru-bin level, or with renal insufficiencyconcomitant with liver dysfunction.

Cvclophosphamide

Etoposide The general recommendation-that cyclophosphamide be adminis-tered at 75% of the standard dose forpatients with serum bilirubin levelsbetween 3.1 and 5.0 mg/dL and with-held in patients with serum bilirubin

Etoposide circulates in the serumlargely bound to albumin. The freefraction of drug is increased in thesetting of hypoalbuminemia, result-

The biliary system is the main routeof elimination of vincristine and vin-blastine. For cholestatic patients, asmall reduction in the vincristine doseresulted in a lower vincristine plasmaAUC and less neurotoxicity.[28] It isrecommended that vincristine and vin-blastine be dose-reduced by 50% forpatients with serum bilirubin levelsbetween 1.5 and 3.0 mg/dL, and thatthey be withheld for levels greaterthan 3.0 mg/dL.[I] A pharmacokineticstudy using a radioimmunoassay forvincristine demonstrated that patientswith raised serum alkaline phosphataselevels, even when total bilirubin andtransaminase levels are normal, haveelevated AUC values.[29]

The vinorelbine package insertempirically recommends reducing thevinorelbine dose by 50% for serumbilirubin levels of 2.1 to 3.0 mg/dL

1061JULY 2005 . ONCOLOGY

and by 75% for bilirubin levels over3 mg/dL.[30] In a pharmacokineticstudy of 29 patients with advancedbreast cancer (including 19 with livermetastases), a weak correlation be-tween bilirubin and vinorelbine clear-ance was observed.[3l] They foundthat vinorelbine clearance correlatedsignificantly with the volume of liverreplaced by tumor, and suggested re-ducing the dosage by 50% in all pa-tients with diffuse liver metastases(defined as greater than 75% of liver

I volume replaced by tumor), regard-

less of serum bilirubin.

and severe liver dysfunction receiveconcomitant mechlorethamine, high-dose methylprednisolone, and ritux-imab as indicated. This combinationmay be used as a bridge to conven-tional regimens.

levels greater than 5.0 mg/dL-is notbased on clinical trials. [I] Cyclophos-phamide undergoes biotransformationto its active metabolite in the liver,which in turn gets inactivated, also inthe liver. The overall exposure to theactive metabolite does not change.

In a study of 17 patients with cir-rhosis, 7 had severe hepatic dysfunc-tion.[33] The half-life and clearanceof cyclophosphamide in these patientsdiffered significantly from those ofpatients with normal liver function,suggesting that cyclophosphamideaccumulates in patients with liverdisease. Since the metabolites of cy-clophosphamide, not the parent com-pound, are responsible for bothantitumor efficacy and toxicity, it isnot surprising that few adverse ef-fects were demonstrated in the set-ting of liver dysfunction. It is notknown if clinical efficacy is alteredin patients with impaired hepatic func-tion due to decreased activation ofthe drug.

Conclusions

Mechlorethamine

Mechlorethamine (Mustargen) un-dergoes rapid chemical transfonna-tion and combines with water orreactive compounds of cells so thatthe drug is no longer present in activefonn a few minutes after administra-tion. In a retrospective study of pa-tients with advanced lymphoma andsevere liver dysfunction (mean totalbilirubin of 10.7 mg/dL and medianalkaline phosphatase of 982 U/L),mechlorethamine was given at a doseof 6 mg/m2/wk in combination withcorti co steroids with or without ritux-imab (Rituxan).[34] Approximately80% of the patients had a poor perfor-mance status prior to the start of ther-apy. With treatment, 54% of patientshad sufficient improvement in liverfunction to receive subsequent thera-py, most often with CHOP (cyclo-phosphamide, doxorubicin HCl,vincristine [Oncovin], prednisone),and 22% of patients were alive anddisease-free at a median follow up of31 months. The median level of bi-lirubin at the time of subsequentCHOP therapy was 2.1 mg/dL (range:0.8-8.3 mg/dL). The authors recom-mend that patients with lymphoma

Although many patients receivingcytotoxic chemotherapy have abnor-mal liver function test values, there isno accepted system to define liverdysfunction in patients with cancer.The serum bilirubin level is the mostfrequently utilized parameter to ad-just chemotherapy dosing, but for cer-tain drugs, transaminase levels, serumalkaline phosphatase levels, and/orserum albumin levels have beenshown to play an important role. Thequestion remains as to whether pa-tients with tumor-related organ dys-function should be approacheddifferently than those with baseline(non-tumor-related) organ dysfunc-tion. It would seem logical to take amore aggressive antineoplastic treat-ment approach in patients whose liv-er impairment is secondary to tumorinfiltration. Nevertheless, caution intreating all patients with hepatic fail-ure is essential.

For the majority of chemotherapeu-tic agents, there is a paucity of data toguide dosing in the setting of liver im-pairment-especially severe liver im-pairment (serum bilirubin: > 5 mg/dL).From the available data, it appears thatcontinuous-infusion 5-FU, capecita-bine, gemcitabine, mechlorethamine,cyclophosphamide, topotecan, and ox-aliplatin are relatively safe, at least forpatients with mild-to-moderate liverdysfunction (see Table 1). On the con-trary, taxanes, vinca alkaloids, irino-tecan, and anthracyclines may resultin unacceptable toxicity (see Table 2for recommended dose adjustments).There are very few data regardingcombination regimens. Likewise,there are few data regarding the anti-tumor efficacy of chemotherapy inthis setting. Further well-designedstudies are undoubtedly needed.

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5. Fleming GF, Schilsky RL, Schumm LP,et at: Phase I and pharmacokinetic study of 24-hour infusion 5-fluorouracil and leucovorin inpatients with organ dysfunction. Ann Oncol

14:1142-1147,2003.6.lWelves C, Glynne-Jones R, Cassidy J, et

at: Effect of hepatic dysfunction due to livermetastases on the pharmacokinetics ofcapecitabine and its metabolites. Clin CancerRes 5:1696-1702,1999.

7. Schull B, Scheithauer W, Komek GV:Capecitabine as salvage therapy for a breastcancer patient with extensive liver metastasesand associated impairment of liver function.Onkologie 26:578-580, 2003.

8. VenookAP, Egorin MJ, Rosner GL, et at:Phase I and pharmacokinetic trial ofgemcitabine in patients with hepatic or renaldysfunction: Cancer and Leukemia Group B9565. J Clin OncoI18:2780-2787, 2000.

9. Wasserman E, Myara A, Lokiec F, et at:Severe CPT-II toxicity in patients withGilbert's syndrome: lWo case reports. AnnOncol 8:1049-1051, 1997.

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is 85%. For those with grade B dis-ease (significant functional compro-mise), the 1- and 2-year survival ratesdrop to 80% and 60%, respectively,while for grade C disease (decom-pensated), the 1- and 2-year rates are54% and 35%, respectively.

MICHAEL PERRY, MD

DirectorDivision of Hematology/OncologyUniversity of Missouri!Ellis Fischel Cancer CenterColumbia, Missouri

Rationale for TreatmentI would submit that treatment of

cancer in the adjuvant setting cannotbe defended in this setting of hepaticfailure, and only treatment of meta-static disease seems reasonable. Butthe cost of a few months of additionalsurvival must be weighed against thelikelihood of increased side effectsand, perhaps, increased morbidity andmortality due to increased toxicity.Treatment of tumors that are very re-sponsive to chemotherapy (Hodgkin'sand non-Hodgkin's lymphomas, germcell tumors, small-cell lung cancer)seems most likely to end in a favorableresult, while treatment of most meta-static solid tumors (breast cancer, non-small-cell lung cancer, colorectalcancer) may buy only increased sideeffects and no survival advantage.

and the extent of liver involvementon scans have all been used, with aresulting lack of standardization. Ab-normal liver function tests are almostalways an exclusion criterion for phase Ithrough phase III randomized clinicaltrials studies, so few, if any, patientshave been studied in the original reg-istration studies. Looking at subpop-ulations comes later, if at all.

It is essential to understand the eti-ology of the liver disease, with theunderstanding that extrahepatic bil-iary obstruction due to chemosensi-tive tumors may respond rapidly tofull-dose chemotherapy, particularlyif the goal is a complete response andpotential cure.

I believe it is important to recog-nize that patients with severely al-tered renal function have a backup, inthe form of dialysis (a proximate life-sustaining measure), that patients withhepatic failure do not. Patients withhepatic failure, therefore, are morelikely to have poorer survival. Forpatients with Childs-Pugh grade A(well-compensated) disease, I-yearsurvival is 100% and 2-year survival

T he article by Eklund, Trifilio,

and Mulcahy begins to address

the difficulties involved in deal-

ing with a special patient population-those with impaired hepatic function.The issues involved in dealing withabnormal liver function are distinctfrom those encountered with end-stagerenal disease (to be discussed in theAugust issue of ONCOLOGY); hepat-ic function due to tumor may improvewith successful therapy, while for di-alysis patients, their renal disease isconsidered permanent.

As Eklund and colleagues suggest,we do not have uniform criteria fordose modifications in liver disease.For hepatic dysfunction, levels of se-rum bilirubin, transarninases, albumin,

Financial Disclosure: The author has no sig-nificant financial interest or other relationshipwith the manufacturers of any products or pro-viders of any service mentioned in this article.

1063JULY 2005 . ONCOLOGY