To critically review available data on the disposition of cancer chemotherapy in patients with hepatic dysfunction, and to derive at dose recommendation.
DATA SOURCES:
All published studies in English.
STUDY SELECTION:
Both human and animal studies.
DATA SYNTHESIS:
The available studies were sequentially qualitatively described and critically discussed.
CONCLUSIONS:
The liver is responsible for the metabolism and elimination of many anticancer agents. Their accumulation during hepatic insufficiency may expose the patient to increased risk of drug toxicity. A variety of clinical methods have been described to estimate the need to decrease doxorubicin dose according to degree of hepatic failure to avoid serious toxicity. In some studies prospective ascertainment of clinical indices such as hepatic enzymes and bilirubin was successful in preventing doxorubicininduced hepatotoxicity. Liver dysfunction has a major impact on cyclophosphamide pharmacokinetics. However, because such impairment leads to less production of the active aldophosphamide, fewer adverse effects were observed in hepatically impaired patients. Vinca alkaloids are extensively metabolized by the liver and excreted in the bile. Systemic exposure to these drugs is inversely correlated to the degree of hepatic failure measured by serum alkaline phosphatase. Although hepatic metabolism is a major route of elimination of fluorouracil, the kidney also plays an important role in its elimination. It has been suggested to reduce its dose in cirrhotic patients. Available pharmacokinetic data and their clinical implications are also discussed for azathioprine, mercaptopurine, etoposide, epirubicin, amsacrine, cytarabine, and other less-studied drugs. Recommendations for dose adjustments are presented and discussed.
Get full access to this article
View all access options for this article.
References
1.
RiveraGEvansWDahlGYeeGCPrattCB. Phase I clinical and pharmacokinetic study of 4î-(9-acridinylamino) methanesulfan M-anisidide (AMSA) in children with cancer. Cancer Res1980; 40: 4250–3.
2.
MahralPSLeghaSSValdiviesaMPondsGYaffeSM. AMSA toxicity in patients with abnormal liver function. Eur J Cancer Clin Oncol1981; 17: 1343–8.
3.
StaubusANeidhartJYoungEEfferGKresselFZimmermanD. Pharmacokinetics of m-AMSA in humans (abstract). Proc Am Assoc Cancer Res1981; 21: 198.
4.
WhelanGSherlockS. Immunosuppressive activity in patients with active chronic hepatitis and primary biliary cirrhosis treated with azathioprine. Gut1972; 13: 907–14.
5.
BachJFDormontJDardenneMBalmerH. In vitro Rosette inhibition by antihuman antilymphocyte serum transplantation. 1969; 8: 265–80.
6.
BrennerDEWiernikPHWesleyMBachurNR. Acute doxorubicin toxicity: Relationship to pretreatment liver function, response and pharmacokinetics in patients with acute non-lymphocytic leukemia. Cancer1984; 53: 1042–8.
7.
BagleyCMBostickFWDeVitaVT. Clinical pharmacology of cyclophosphamide. Cancer Res1973; 33: 226–33.
8.
DeVitaUTAdamsonRH. The metabolism of 14C-cyclo-phosphamide: Comparative drug metabolism studies on African and American patients with lymphosarcoma and Burkitt's tumor. In: UmezawaH ed. Progress in antimicrobial and anticancer chemotherapy. Vol. 2. Tokyo, Japan: University of Tokyo Press, 1970: 218–25.
9.
BrockNGrossRHoherstHJKleinHOSchneiderB. Activation of cyclophosphamide in man and animals. Cancer1971; 27: 1512–29.
10.
JumaFD. Effect of liver failure on the pharmacokinetics of cyclophosphamide. Eur J Clin Pharmacol1984; 26: 591–3.
11.
BleyerWA. Cancer chemotherapy in infants and children. Pediatr Clin N Am1985; 32: 557–74.
12.
PowisG. Effects of disease states on pharmacokinetics of anticancer drugs. In: AmesMMPowisGKovachJS. eds. Pharmacokinetics of anticancer agents in humans. Amsterdam: Elsevier, 1983: 363–97.
13.
BenjaminRSRiggsCESerpickAABachurNR. Biliary excretion of adriamycin (abstract). Mayo Clin Res1974; 22: 483A.
14.
KayeSBCummingsJKerrDJ. How much does liver disease affect the pharmacokinetics of adriamycin? Eur J Cancer Clin Oncol1985; 21: 893–5.
15.
BenjaminRSWiernikPHBachurNR. Adriamycin chemotherapy. Efficacy, safety, and pharmacologic basis of an intermittent single high-dosage schedule. Cancer1974; 33: 19–27.
16.
BenjaminRS. A practical approach to adriamycin (NSC-123127) toxicology. Cancer Chemother Rep1975; 6: 191–4.
17.
PerryMC. Hepatotoxicity of chemotherapeutic agents. In: PerryMCYarbroJW. eds. Toxicity of chemotherapy. Orlando: Grune and Stratton, 1984: 297–315.
DoroshowJChanK. Relationship between doxorubicin clearance and indocyanine green dye pharmacokinetics in patients with hepatic dysfunction (abstract). Proc Am Soc Clin Oncol1982; 1: 11.
20.
ChanKKChlebowskiRTTongMChenHSGGrossJFBatemanJR. Clinical pharmacokinetics of adriamycin in hepatoma patients with cirrhosis. Cancer Res1980; 40: 1263–8.
21.
BalletFBarbareJCPouponR. Hepatic extraction of adriamycin in patients with hepatocellular carcinoma. Eur J Cancer Clin Oncol1984; 20: 761–4.
22.
HarrisPAGrossJF. Preliminary pharmacokinetic model for adriamycin. Cancer Chemother Rep1975; 59: 819–25.
23.
GarniorMBEnsmingerWDIsraelM. A clinical pharmacological evaluation of hepatic arterial infusion of adriamycin. Cancer Res1979; 39: 4105–10.
24.
BrennerDEAnthonyLBHalterSHarrisNLCollinsJCHandeKR. Effect of allyl-alcohol induced sublethal hepatic damage upon doxorubicin metabolism and toxicity in the rabbit. Cancer Res1987; 47: 3259–65.
25.
BachurNRHildebrandRLJaenkeRS. Adriamycin and daunorubicin disposition in the rabbit. J Pharmacol Exp Ther1974; 191: 331–9.
26.
BrennerDENooneRHandeKR. A comparison of doxorubicin pharmacokinetics in the rabbit and in man (abstract). Proc Am Assoc Cancer Res1984; 28: 330.
27.
Maniez-DevosDHBaurainRTrouetALesneM. Doxorubicin pharmacokinetics in the rabbit. J Pharmacol1985; 16: 159–69.
28.
CamaggiCMStrocchiEMartoniAAnglettiBComparsiRPennutiF. Cellular and plasma pharmacokinetics of weekly 20 mg 4î epidoxorubicin (epirubicin) in advanced cancer patients. Cancer Chemother Pharmacol1986; 18: 47–50.
29.
SpethPAJLinssenPCMBeexLDe PauwBE. Cellular and plasma pharmacokinetics of weekly 20 mg 4î epidoxorubicin (epiRubicin) bolus injections in patients with advanced breast carcinoma. Cancer Chemother Pharmacol1986; 18: 78–82.
30.
PerryMCMoertelCGSchuttAJReitemeierRJHannRG. Phase II studies of dianhydrogalactitol and VP16 in colorectal cancer. Cancer Treat Rep1976; 60: 1247–50.
31.
D'IncalciMRossiCZucchettiMUnsoRCavalliFMongioniC. Pharmacokinetics of etoposide in patients with abnormal renal and hepatic function. Cancer Res1986; 46: 2566–71.
32.
MenradDBGisselbrechtCMartyMReyesFDhumbauxD. Antineoplastic agents and the liver. Gastroenterology1980; 78: 142–64.
33.
WiebeVJBenzCCDegiegorioMW. Clinical pharmacokinetics of drugs used in treatment of breast cancer. Clin Pharmacol1988; 15: 180–93.
34.
AguiarJLABergerMRFrankN. Locoregional application of 5-fluorouracil to the liver: Alteration of pharmacokinetics and bone marrow toxicity in rats with thioacetamide induced cirrhosis. Toxicol Lett1987; 36: 181–8.
35.
CabnerB. Pharmacologic principles of cancer treatment. Toronto: WB Saunders, 1982: 408.
36.
JacksonDVCastleMCBenderRA. Biliary excretion of vincristine. Clin Pharmacol Ther1978; 24: 101–7.
37.
DesaiZRVan den BergHWBridgesJMShanksRG. Can severe vincristine neurotoxicity be prevented? Cancer Chemother Pharmacol1982; 8: 211–4.
38.
Van den BergHWDesaiZRWilsonRBonnerL. The pharmacokinetics of vincristine in man: Reduced drug clearance associated with raised serum alkaline phosphatase and dose-limited elimination. Cancer Chemother Pharmacol1982; 8: 215–9.
39.
ArbuckSGDouglasHOGoodwinPNavaHClarkJCromWR. Pharmacokinetics of etoposide in patients with normal and abnormal liver function (abstract). Proc Am Soc Clin Oncol1985; 4: 40.
40.
CavalliFRozencweigMRenardJGoldhirschAHansenHH. Phase II study of oral VP-16–213 in hepatocellular carcinoma. Eur J Cancer Clin Oncol1981; 17: 1079–82.
41.
Compendium of pharmaceuticals and specialties. 26th ed.Ottawa, Ontario, Canada: Canadian Pharmaceutical Association, 1991.
42.
CyskRLShoemakerDAdamsonRH. The pharmacologic disposition of 4î-(9-acridinylamino) methanesulfan-M-anisidide in mice and rats. Drug Metab Disp1977; 5: 579–90.
43.
Investigational Drug Branch, Cancer Therapy Evaluation Program, Division of Cancer Treatment, National Cancer Institute, m-ASA (NSC 249992) Group C protocol for the therapy of refractory adult acute myelogenous leukemia with m-AMSA given as a single agent. Bethesda, MD, 1982.
44.
AndersonRJSchrierRW. Clinical use of drugs in patients with kidney and liver disease. Philadelphia: WB Saunders, 1981: 328–9.
45.
GlobeLM. Cytotoxic and immunosuppressive drugs. In: AndersonRJSchrierRW. eds. Clinical use of drugs in patients with kidney and liver disease. Philadelphia: WB Saunders, 1981: 260–75.
