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CANCER CHEMOTHERAPY AND THE LIVER
DRUG-INDUCED LIVER DISEASE
1089-3261/98 $8.00
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CANCER CHEMOTHERAPY AND THE LIVER John S. Macdonald, MD
The clinical issues involved in potential hepatotoxicity from cancer chemotherapy may be complex because it is sometimes difficult to assess the cause and effect relationship between the administration of chemotherapeutic agents and hepatic abn~rmalities.~~ Patients with cancer frequently have a variety of reasons for liver abnormalities. In patients with solid tumors, the liver is a common site of metastasis, and the liver metastases will produce abnormal liver function studies and eventually hepatic failure. Also, many patients with malignant disease require frequent blood and blood-product transfusions, particularly in patients with hematologic malignancies. Such patients may develop transfusion-associated viral hepatitis-produced liver abnormalities," which may be difficult to separate from the potential toxic effects of chemotherapeutic agents. Finally, most patients with cancer are being treated with a variety of noncytotoxic drugs. They may be receiving antiemetics, analgesics and antibiotics, all of which may produce hepatic abnormalities. Although the attribution of specific liver abnormalities to specific chemotherapeutic drugs may sometimes be complex and problematical, there is no question that a number of commonly used chemotherapy drugs are associated with hepatotoxi~ity.~~ The clinician managing patients with cancer should have an understanding of the drugs that are commonly associated with hepatotoxicity, whether that hepatotoxicity is reversible, and whether it is predictable or idiosyncratic in nature. Clinicians must also be aware that the potential for hepatotoxicity with chemotherapeutic drugs in many instances may be dose related. AlFrom the Gastrointestinal Oncology Service, St. Vincents Comprehensive Cancer Center, New York, New York
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though this latter statement seems self-evident, it is a progressively important consideration now considering the widespread use of highdose chemotherapy, with stem-cell support in both hematologic and nonhematologic malignancies. This article discusses some of the more important commercially available drugs that may cause hepatotoxicity, the severity of such hepatotoxicity, and the prevention or management of drug-induced hepatotoxicity where that information is known. It also discusses the interaction of high (bone marrow transplant)-dose chemotherapy and liver function, and the need to modify dose and schedule of chemotherapeutic drugs in patients with pre-existing liver function abnormalities. WIDELY AVAILABLE DRUGS KNOWN TO CAUSE HEPATOTOXICITY
Drugs that commonly produce hepatotoxicity are L-asparaginase, methotrexate, cytarabine, 6-Thiopurines, and mithramycin. L-asparaginase
L-asparaginase is an enzyme used predominantly in the therapy of acute lymphocytic leukemia. It is an important component of the modern combination chemotherapy of leukemia in children. L-asparaginase functions by serving as an enzyme producing the hydrolysis of asparagine to aspartic acid and ammonia. The drug appears to function as a potent inhibitor of protein synthesis, presumably by causing a decrease in asparagine, a nonessential amino acid.* L-asparaginase has several major toxicities. These include hypersensitivity, which is a common toxicity and appears to be the result of the production of antibodies by the patient against L-asparaginase, which is a bacterial protein. Another major toxicity is pancreatitis, which occurs in approximately 50% of cases.8L-asparaginase also can produce hepatotoxicity. The hepatic toxicity of L-asparaginase is both indirect and direct. The indirect hepatotoxicity is a result of the inhibition of protein ~ynthesis.~ Inhibition of hepatic protein synthesis results in a decrease in albumin production with resultant hypoalbuminemia, but also decreases the synthesis of clotting factors and antithrombotic factors, such as Antithrombin-I11 and proteins C and S. The result of this may be the occurrence of both thrombotic and hemorrhagic complications in patients receiving L-asparaginase. The direct hepatotoxicity of L-asparaginase results in elevations of transaminases, alkaline phosphatase and bilirubin. When a liver biopsy is performed, fatty infiltration of the liver is frequently seen. Asparaginase does not appear to produce permanent hepatotoxicity, and when drug therapy is discontinued, liver function tests normalize. Chronic fibrosis and cirrhosis do not occur. Abnormal liver function tests will
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occur in close to 100% of patients receiving L-asparaginase for the therapy of leukemia. It is probable that hepatic steatosis is caused by decreased mobilization of lipids from the liver.6Whether this is a direct result of inhibition of the synthesis of enzymes important for hepatic lipid homeostasis is unknown.
Methotrexate Methotrexate is an antimetabolite that is a potent inhibitor of the enzyme dihydrofolate reductase. Methotrexate is one of the oldest chemotherapeutic agents in the armamentarium of the oncologist. This drug has been used for the last 45 years in the treatment of a number of malignancies including leukemias, particularly childhood leukemia, and a variety of solid tumors, including head and neck cancers, pediatric tumors and sarcomas. It has been used in both conventional dose and high-dose schedules. The qualitative toxicities' reproducibly associated with methotrexate are familiar to oncologists. Methotrexate may be given by a variety of routes including oral, subcutaneous, intramuscular, and intravenous schedules. The drug is routinely associated with myelosuppression and mucositis in conventional dosing schedules. In higher doses, methotrexate may cause nephrotoxicity, which may be a direct effect of precipitation of the drug in renal tubules.' Vigorous hydration and alkalization of the urine may avoid this toxicity. The toxicity of methotrexate is ameliorated by the administration of the tetrahydrofolate folinic acid (leukovorin),which is the product of the reaction catalyzed by dihydrofolate reductase. Methotrexate may also produce hepatotoxicity. Reversible elevations in bilirubin and transaminases are not uncommon in patients receiving high-dose methotrexate with leukovorin rescue. These findings primarily are clinical chemistry abnormalities and are not associated with longterm hepatic sequelae.' Liver biopsy may demonstrate fatty change but no fibrosis or cirrhosis.55There is strong evidence57that longterm, daily, oral administration of methotrexate (a dose and schedule used in the past in acute childhood leukemia or in the treatment of nonmalignant diseases such as psoriasis and arthritis) may be associated with the development of chronic fibrosis leading to clinical manifestation of heAs many as 25% of patients with chronic daily oral patic ~irrh0sis.l~ administration methotrexate will develop hepatic fibrosis.57Hepatotoxicity also appears to be more common in patients receiving methotrexate who have some degree of underlying chronic liver disease, typically as a result of alcohol abuse.I3The mechanism of hepatic injury leading to fibrosis/cirrhosis in methotrexate-induced liver injury is not clear. The likelihood of this toxicity can be markedly decreased or essentially eliminated by using intermittent forms of therapy rather than daily oral schedules of treatment.
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Cytarabine Cytarabine or Ara-C is a deoxycytidine analogue5 widely used in the treatment of acute leukemias. In the induction regimens for acute leukemia, ara-C is used frequently in continuous infusion regimens of 100 to 200 mg/m2/day for 7 days. The drug may be used in conventional-dose schedules or in high-dose schedules (2 to 3 gm/m2 every 12 hours) in both induction and consolidation regimens for acute myelogenous leukemia. The mechanism of action of ara-C requires in vivo phosphorylation of the drug to the triphosphate ara-CTP. Ara-CTP may then be incorporated into DNA as a false nucleotide in place of deoxycytidine triphosphate, resulting in inhibition of DNA polymera~es.’~ The major dose-limiting toxicity of ara-C is myelosuppression. At the standard doses of 100 to 200 mg/m2/d given by continuous infusion over 7-day periods, myelosuppression with leukopenia and thrombocytopenia are always seen. Higher doses of ara-C, typically 2 to 3 g/m2 every 12 hours, also produce significant myelosuppression and gastrointestinal toxicity. Neurologic toxicity also may be produced by high-dose a~a-C.~ Liver function abnormalities are commonly seen with ara-CZ3,46 In the continuous low-dose regimens, liver function abnormalities are manifested by moderate elevation of transaminases with mild jaundice. It is uncommon for liver function abnormalities to require interruption or attenuation of high-dose ara-C therapy; however, cholestatic jaundice and elevation of transaminases are common, and reports of liver biopsy performed in patients with liver abnormalities after receiving ara-C demonstrate intrahepatic cholestasis.20Hepatic function abnormalities produced by cytosine arabinoside are reversible. The mechanisms of hepatotoxicity with ara-C are not defined, but it is thought that the drug inhibits transport mechanisms in the hepatocytes. Although as many as 85% to 90% of patients receiving high-dose ara-C may develop abnormal liver function tests,16 this toxicity essentially is always reversible and does not preclude further treatment with ara-C.35,46 6-Thiopurines The 6-thiopurines as represented by the clinically useful drugs 6mercaptopurine (6-MP) and 6-thioguanine (6-TG)are used in the therapy of acute leukemia.18,28 Azathioprine, another drug in this class, is an analogue of 6-MP and is used primarily as an immuno~uppressive.~~ Azathioprine is rapidly metabolized to 6-MP in vivo. Both 6-MP and 6TG inhibit de novo purine synthesis and also inhibit purine interconversions. When anabolized to the triphosphate or nucleotide forms, the thiopurines may be incorporated into nucleic acids. The major toxicity of 6-MP is myelosuppression, but gastrointestinal toxicities, such as stomatitis, diarrhea, and vomiting, are also common. Hepatotoxicity also is commonly seen with 6-MP. As many as 30%
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of patients may develop hepatotoxicity manifested as cholestatic jaundice with or without elevations of hepatic transamina~es.'~ These liver abnormalities typically are more of a laboratory phenomenon than a significant clinical event and are reversible when the drug is stopped. When liver biopsies are performed, it is uncommon to see any significant hepatic necrosis and, typically, mild intrahepatic cholestasis is the major abnormality observed. There also may be some hepatocyte atypia noted.37Because such a relatively large proportion of patients receiving 6-MP develop chemical manifestations of hepatotoxicity, it is important not to administer 6-MP with other known hepatotoxic agents. 6-TG has rarely been associated with liver toxicity, particularly when compared with the relatively frequent hepatic abnormalities seen with 6-MP. If 6-TG is related to hepatic toxicity, the association appears to be an idiosyncratic one. 6-TG has been associated with a single case of peliosis hepatica and also has been noted in case reports to be possibly implicated as a cause of hepatic veno-occlusive disease (VOD).21,36
Mithramycin (Plicamycin)
Mithramycin is an antineoplastic antibiotic that is rarely used for antineoplastic therapy at present, although it does have activity against embryonal cell carcinoma of the testes.33The drug, which is a potent inhibitor of DNA-directed RNA synthesis, now is used mainly in the 47 Mithramycin therapy of hypercalcemia associated with malignan~y.'~, is one of the most potent hepatotoxins ever used in the therapy of cancer. When used in therapeutic doses for testicular cancer, mithramycin was associated with very significant transaminase elevation in essentially 100% of patients. The drug also has a secondary hepatic toxicity in that it is a very potent inhibitor of nucleic acid synthesis, which leads to decreased protein synthesis, causing a rapid decrease in levels of coagulation factors 11, V, VII, and X and a resultant significant coagulopathy. Hemorrhagic complications as a result of this coagulopathy were freq ~ e n t The . ~ ~ significant hepatotoxicity and coagulopathies associated with Mithramycin therapy clearly are dose-related. When fiithramycin is used in the relatively low-dose of 25 kg/kg as a single intravenous injection in the treatment of hypercalcemia, coagulopathy is extremely rare, and mild reversible enzyme elevation is noted in less than 20% of cases."
NEW AGENTS
Two major classes of recently developed chemotherapeutic agents are being widely evaluated in the therapy of cancer. These include the taxanes as characterized by tax01~~ and taxotere,52and the topoisomerase1 inhibitors as represented by t ~ p o t e c a nand ~ ~ CPT-11.50These drugs are
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being widely evaluated and have significant roles in the treatment of breast cancer, ovarian cancer, lung cancer, and gastrointestinal cancers. Both the topoisomerase-1 inhibitors and the taxanes are plant-derived natural products. These drugs vary in their dependence upon hepatic metabolism, but the liver is important in the metabolism of ta~anes,2~ and CPT-11.27The taxanes and the topoisomerase-1 inhibitors are not associated with significant liver toxicity in clinically used doses and schedules; however, docetaxel (taxotere) frequently produces accumulation of fluid into third spaces. This is not hepatic toxicity, but may produce ascites that could be confused with hepatic decompensation in patients with advanced cancer.52 HIGH-DOSE CHEMOTHERAPY
With the widespread use of the clinical strategy of bone marrow transplantation or peripheral blood stem cell support of high-dose chemotherapy, hepatotoxicity resulting from high doses of chemotherapy has been a finding of increasing clinical importance. Drugs commonly used in high doses with bone marrow or stem cell transplant and associated with VOD Busalfan Cyclophosphamide Etoposide Cyclophosphamide is an alkylating agent that requires conversion by hepatic microsomal enzymes to an active alkylating moiety 4-OH cyclophosphamide. Although hepatic metabolism is an important aspect of the clinical pharmacology of cyclophosphamide, the drug is not intrinsically hepatotoxic. It has only rarely been reported to be associated with liver function test abnormalities. When this occurs, it is probably secondary to an idiosyncratic rea~tion.~,54 Busulfan is an alkylating agent that is no longer commonly used in conventional doses. In the past, before the effectiveness of a-interferon and hydroxyurea were documented for the treatment of chronic myelogenous leukemia and other myeloproliferative syndromes, busulfan was commonly used in low-dose oral schedules. Hepatic dysfunction with this drug used in low doses was unc0mmon.3~In high doses, busulfan may be associated with an important hepatotoxicity, hepatic VOD.34 The third commonly used high-dose chemotherapy agent is the topoisomerase-2 inhibitor, etoposide. This natural product is excreted primarily in the bile and, in conventional doses, is not considered to be hepatotoxic.3°In higher doses used as a single agenP and in combination with cytosine arabinoside,’O the drug has been associated with abnormalities in liver function, including elevation of transaminases and alkaline phosphatase. These abnormalities reversed after completion of chemotherapy and were not associated with long-term hepatic abnormalities or chronic fibrosis/cirrhosis.
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Although cyclophosphamide, busulfan, and etoposide are of low intrinsic hepatotoxicity, a major complication of bone marrow transplant that may be fatal, hepatic VOD, is likely associated with the use of highdose chemotherapy used in the transplant setting.41VOD results from obstruction or thrombosis in the postcapillary hepatic venules. Clinical manifestations of VOD are the sudden onset of right upper quadrant pain, hepatomegaly, and the rapid development of transudative ascites secondary to hepatic postsinusoidal obstruction and increased portal pressure. Liver function abnormalities rapidly develop and are indicated by elevations in hepatic enzymes and bilirubin. The clinical manifestations of hepatic VOD are essentially identical to those of the Budd-Chiari syndrome, developing as a result of hepatic vein thrombosis. It appears that VOD in the setting of transplantation is the result of damage to hepatic venule endothelial surfaces by cytotoxic therapy and probably not primarily caused by the induction of hepatic vein or venule thrombosk41 The overall incidence of VOD in the setting of bone marrow transplant is relatively high and approaches 20%32,41 VOD of the liver following bone marrow transplant. VOD is fatal in more than 50% of cases. It is not known why particular patients develop VOD post-transplant, but VOD does appear to be associated with drugs that require metabolism in the liver.34It also may be more common in patients who have underlying hepatic abnormalities either induced by previous conventional chemotherapy, concurrent hepatitis, or significant metastatic disease in the liver. Busulfan in particular, which is typically given at doses of 4 mg/kg/d for 4 consecutive days in pretransplant regimens, has been associated with the production of VOD in patients with acute leukemia. In some series, approximately 20% of patients receiving busulfan at this dose and schedule develop some manifestations of VOD.25The therapy of VOD is unsatisfactory and essentially supportive. Rapidly progressive hepatic failure implies a poor prognosis, whereas patients with relatively stable liver function abnormalities whose ascites respond to diuretics generally will survive VOD. DOSE MODIFICATION AND HEPATIC FUNCTION
The effect of abnormal hepatic function upon the clinical pharmacology of antineoplastic agents may be important clinically in planning the dosage and schedule of chemotherapy. The assessment of need for dose modification of chemotherapeutic agents in patients with abnormal hepatic function is an important clinical issue. Many cancer chemotherapeutic drugs depend on hepatic metabolism, at least in part. Both the clinical beneficial effect, that is cancer cell cytotoxicity, and the toxic effects of cancer chemotherapeutic agents, generally depend upon the product of the plasma drug concentration multiplied by the time of drug exposure (C X T) achieved by a particular dose and schedule. Therefore, changes in hepatic function as they affect drug metabolism and clearance
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may alter both the antineoplastic effect and the toxicity patterns seen with cancer chemotherapy. There are a number of drugs commonly used, including anthracyclines, vinca alkaloids, epipodophyllotoxins, taxanes, and some topoisomerase-1 inhibitors, which undergo either hepatic metabolism or biliary clearance. Dose modification in patients with altered hepatic function is an important clinical issue in patients treated with these drugs. Drugs that may require dose modification in cases of abnormal hepatic function Anthracyclines Doxorubicin Daunorubicin Idarubicin Epipodophyllotoxins Etoposide Teniposide Topoisomerase-I inhibitors CPT-11 Vincas Vincristine Vinblastine Vinorelbine Vindesine Taxanes Docetaxel Paclitaxel The anthracyclines (idarubicin, doxorubicin, and daunorubicin) are metabolized significantly in the liver. Renal clearance of these drugs is a very minor factor in their clinical pharmacology and it is not necessary to modify doses of anthracyclines secondary to renal insuffi~iency.~ Unfortunately, with regard to hepatic function abnormalities, there are not adequate data to give clear clinical guidelines as to the need for dose modification of anthracyclines therapy. Generally, 50% reductions of drug are considered when the bilirubin is between 1.5 and 3.0 mg/dL or when transaminases are less than 3 times the upper limit of normal. When the bilirubin is between 3.1 and 5 mg/dL or the transaminases exceed 3 times the upper limit of normal, 50% to 25% of projected dose is recommended. If bilirubin is greater than 5 mg/dL, omission of the anthracycline therapy may be required; however, these rough guidelines must be taken in the context of the potential clinical benefit to the patient from administration of anthracyclines. There is some evidence that administration of full doses of doxorubicin in the face of abnormal liver function tests can be done safely without significantly increased drug If the patient has a malignancy likely to respond well to anthracycline, one may reasonably give h l l doses of therapy with abnormal liver function, with the understanding that toxicity may be increased, but the clinical benefit may justify the increase in toxicity.
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This strategy is a particularly valid approach if one is treating hepatic metastases that have caused the liver function abnormalities. The vinca alkaloids are commonly used drugs that are metabolized in the liver. Less than 50% of administered doses of vincristine, vinblastine, vindesine, and navelbine, are excreted in the urine.15Because of the magnitude of hepatic metabolism of the vincas, there is appropriate concern that in patients with abnormal liver function the toxicity of these drugs may be increased. As with anthracycline, there are no good data showing a clear relationship between abnormal liver function tests and plasma levels of vinca alkaloids; however, the toxicity of vincas appears to increase when they are administered in patients with hyperbilir~binemia.~~ Many oncologists, therefore, omit therapy with vinca alkaloids in patients with bilirubin levels greater than 3.0 mg/dL. The epipodophyllotoxins, as represented clinically in adult oncology by etoposide, have a somewhat different metabolism than the vinca alka10ids.I~Metabolism, most likely hepatic metabolism, of etoposide is an important mechanism of drug clearance, along with renal clearance of unmetabolized drug. Approximately 50% of intravenously administered etoposide is excreted in the urine.12Although approximately 50% of the metabolism of etoposide at most is dependent on the liver, there is still concern about administering this drug in patients with significant liver abnormalities. This is because plasma etoposide is highly protein-bound. In patients with hyperbilirubinemia there is substantial displacement of bound etoposide by elevated plasma bilirubin. This effectively increases the free or clinically active etoposide plasma levels and may result in significant toxi~ity.'~, 48 Therefore, in patients with significant hyperbilirubinemia (> 5 mg/dL), etoposide is frequently omitted, and the dose may be modified to 75% of projected dose if the bilirubin is between 3 and 5 mg/dL. Paclitaxel is extensively metabolized in the liver, and biliary excretion of drug metabolites is important. There are data suggesting that patients with hyperbilirubinemia or increased hepatic transaminase levels are more likely to have toxic effects from Taxol than patients with normal liver function.51It appears appropriate to decrease the dose of Taxol by 50% in patients with significant liver abnormalities (bilirubin 2 3 mg/dL or transaminases 2 3 times normal). As with paclitaxel, docetaxel is also extensively metabolized in the liver, and patients with significant liver function abnormalities (alkaline phosphatase > 2.5 times normal, transaminases > 1.5 times normal) should have a minimum of 25% dose reduction.43 Gastrointestinal toxicity from CPT-11 has an interesting relationship with hepatic metabolism. The major clinical toxicity of CPT-11 is diarrhea. To be active as an antineoplastic agent, CPT-11 must be metabolized to its active form, SN-38, by carboxylesterase. This metabolism to SN-38 may occur intracellularly in colon cancer cells. A potential mechanism of resistance to CPT-11 is decreased production of SN-3€L40SN-38 is conjugated in the liver to its glucuronide, and decreased hepatic metabolism of SN-38 may lead to an increased incidence of diarrhea in patients
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receiving CPT-11. It is assumed that unconjugated SN-38 excreted in the bile is toxic to the mucosa of the bowel and causes diarrhea.26Another area of interest with regard to hepatic function and CPT-11 concerns patients with Gilbert’s syndrome. These patients may be more sensitive to CPT-11 toxicity. It is probable that the decreased hepatic production of the SN-38 glucuronide occurs in Gilbert’s cases and results in increased CPT-11 toxicity. The Gilbert’s association presently is only a clinical observation. More information bearing upon a possible association between Gilbert’s syndrome and CPT-11 bowel toxicity will have to be obtained before this relationship may be confirmed. ACKNOWLEDGMENT The author greatly acknowledges the expert technical assistance of John Bazos in preparing this manuscript.
References 1. Allegra CJ: Antifolates Philadelphia, JB Lippincott, 1990, pp 110-153 2. Allegra CJ: Antifolates. Philadelphia, Lippincott-Raven, 1996, p 109 3. Bacon AM, Rosenberg SA: Cyclophosphamide hepatotoxicity in a patient with systemic lupus erythematosus. Ann Intern Med 976243, 1982 4. Baker WJ, Royer GL, Weiss RB: Cytarabine and neurologic toxicity. J Clin Oncol 9:679, 1991 5. Bergman W, Feeney R Contributions to the study of marine products, XXXII. The nucleosides of sponges. J Org Chem 16:981, 1951 6. Chabner BA Enzyme Therapy: L-Asparaginase. In Chabner BA, Collins JM (eds): Cancer Chemotherapy: Principles and Practice. Philadelphia, JB Lippincott, 1990, pp 397407 7. Chabner BA: Miscellaneous Agents: L-Asparaginase. Philadelphia, Lippincott-Raven, 1993. ~ D , 387 = 9. Chabner BA, Myers CE: Antitumor antibiotics. In DeVita VT Jr, Hellman S, Rosenberg SA (eds):Cancer: Principles and Practice of Oncology, ed 4. Philadelphia, JB Lippincott, 1993, pp 374-384 10. Chan HY, Meyers FJ, Lewis JP: High-dose VP-16 with intermediate dose cytosine arabinoside in the treatment of relapsed acute nonlymphocytic leukemia. Cancer Chemother Pharmacol20:265-266, 1987 11. Choo Q-L, Kuo G, Weiner AM, et al: Isolation of a cDNA clone derived from a bloodborne non-A, non-B viral hepatitis genome. Science 244:359-362, 1989 12. Clarke PI, Slevin ML The clinical pharmacology of etoposide and teniposide. Clin Pharmacol 12:223-252, 1987 13. Dahl MGC, Gregory MM and Scheur PJ: Liver damage due to methotrexate in patients with psoriasis. BMJ 1:625-630, 1971 14. Davies J, Trask C, Souhami RL Effects of mithramycin on widespread painful bone metastases in cancer of the breast. Cancer Treat Rep 63:1835-1838, 1979 15. Donehower RC, Rowinsky E K Anticancer drugs derived from plants. In DeVita HS, Rosenberg SA (eds): Cancer: Principles and Practice of Oncology. Philadelphia, Lippincott-Raven, 1993, pp 409417 16. Donnehower RC, Karp JE, Burke PJ: Pharmacology and toxicity of high-dose cytarabine by 72-hour continuous infusion. Cancer Treat Rep 70:1059-1065, 1986 17. Einhorn D I Hepatotoxicity of 6-mercaptopurine. JAMA 188:802, 1964 18. Elion GB: Biochemistry and pharmacology of purine analogs. Federation Proceedings 262396, 1967 ~
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19. Furth JJ, Cohen SS Inhibition of mammalian DNA polymerase by the 5’-triphosphate of 9-beta-D-arabinofuranosyl-cytosine and the triphosphate of 9-beta-D-arabinofuranosyladenine. Cancer Res 28:2061-2067, 1968 20. George CB, Mansour RP, Redmond J: Hepatic dysfunction and jaundice following high-dose cytosine arabinoside. Cancer 54:2360-2362, 1984 21. Gill RA, Onstad GR, Cardamone JM: Hepatic veno-occlusive disease caused by 6thioguanine. Ann Intern Med 9658450, 1982 22. Goldberg JW, Lidsky M D Cyclophosphamide-associatedhepatotoxicity. South Med J 78:222-223, 1985 23. Goode UB,Leventhal B, Henderson E: Cytosine arabinoside in acute granulocytic leukemia. Clin Pharmacol Ther 12:599-606, 1971 24. Green L, Donehower RC: Hepatic toxicity of low doses of mithramycin in hypercalcemia. Cancer Treat Rep 68:1379-1381, 1984 25. Grochow LB, Jones RJ, Brundett RB: Pharmacokinetics of busulfan: Correlation with veno-occlusive disease in patients undergoing bone marrow transplantation. Cancer Chemother Pharmacol 25:5541, 1989 26. Gupta E, Lestingi TM, Mick R, et al: Metabolic fate of irinotecan in humans: Correlation of glucuronidation with diarrhea. Cancer Res 543723, 1994 27. Gupta E, Lestingi TM, Mick R, et al: Metabolic fate of irinotecan in humans: Correlation of glucuronidation with diarrhea. Cancer Res 54:3723, 1994 28. Hitchings GH, Elion G B The chemistry and biochemistry of purine analogs. Ann NY Acad Sci 60:195, 1954 29. Huizing MT, Keung ACF, Rosing H: Pharmacokinetics of paclitaxel and metabolites in a randomized comparative study in platinum-pretreated ovarian cancer patients. J Clin Oncol 11:2127, 1993 30. Isell BF, Crooke ST Etoposide (VP-16-213). Cancer Treat Rev 6:107-124, 1979 31. Johnson DH, Greco FA, Wolff S N A potential complication of high-dose therapy. Cancer Treat Rep 671023-1024, 1983 32. Jones RJ, Lee KS, Beschomer WE, et al: Venoocclusive disease of the liver following bone marrow transplantation. Transplantation 44:778-783, 1987 33. Kennedy BJ, Griffen VO, Lober P: The specific effect of mithramycin on embryonal carcinoma of the testis. Cancer 18:1631-1636, 1965 34. King PD, Perry MC: Hepatotoxicity of chemotherapeutic and oncologic agents. Gastroenterol Clin North Amer 24:969-990, 1995 35. Kremer WB: Cytarabine. Ann Intern Med 82:684-688, 1975 36. Krivoy N, Raz R, Carter A: Reversible hepatic veno-occlusive disease and 6-thioguanine [letter]. Ann Intern Med 96:788, 1982 37. McIlvanie SK, MacCarthy J D Hepatitis in association with prolonged 6-mercaptopurine therapy. Blood 14:89-90, 1959 38. Monto RW, Talley RW, Caldwell MJ: Observations on the mechanism of hemorrhagic toxicity in mithramycin (NSC-24559) therapy. Cancer Res 29:697-704, 1969 39. Morris LE, Guthrie TH: Busulfan-induced hepatitis. Am J Gastroenterol 83:682-683, 1988 40. Ogasawara H, Nishio K, Kanzawa F, et al: Intracellular carboxyl esterase activity is a determinant of cellular sensitivity to the antineoplastic agent KW-2189 in cell lines resistant to cisplatin and CPT-11. Japanese Journal of Cancer Research 86124, 1995 41. Rollins BJ: Hepatic veno-occlusive disease. Am J Med 81:297-306, 1986 42. Rosman M, Bertino J R Azathioprine. Ann Intem Med 79:694-700, 1973 43. Rowinsky EK and D. RC: Antimicrotubule agents. In DeVita VT, Hellman S (eds): Cancer Principles and Practice of Oncology. Philadelphia, Lippincott-Raven, 1997, pp 467-483 44. Rowinsky EK, Cazenave LA, Donehower RC: Taxol: A novel investigational antineoplastic agent. J Natl Cancer Inst 82:1247, 1990 45. Rowinsky EK, Grochow LB, Hendricks CB: Phase I and pharmacologic study of topotecan: A novel topoisomerase I inhibitor. J Clin Oncol 10:647, 1992 46. Slavin RE, Dias MA, Sara1 R Cytosine arabinoside-induced gastrointestinal toxic alterations in sequential chemotherapeutic protocols. Cancer 42:1747-1759, 1978
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47. Slayton RE, Shnider B, Eliase E: New approach to the treatment of hypercalcemia: The effect of short term treatment with mithramycin. Clin Pharmacol Ther 12:833-837,1971 48. Stewart CF, Arbuck SG, Fleming RA: Changes in the clearance of total and unbound etoposide in patients with liver dysfunction. J Clin Oncol 8:1874-1879, 1990 49. Sulkes A, Collins J M Reappraisal of some dosage adjustment guidelines. Cancer Treat Rep 71:229-233, 1997 50. Tanizawa A, Fujimori A, Fujimori Y, et al: Comparison of topoisomerase I inhibition, DNA damage, and cytotoxicity of camptothecin derivatives presently in clinical trials. J Natl Cancer Inst 86:836, 1994 51. Venock AP, Egorin M, Braun TD: Paclitaxel (Taxol) in patients with liver dysfunction (CALGB 9264) (Abstract). Proc Am SOC Clin Oncol 13139, 1994 52. Verweij J, Clavel M, Chevalier 8: Paclitaxel (Taxol) and docetaxel (Taxotere): Not simply two of a kind. Ann Oncol5:495, 1994 53. Wade JC, Gaffey M, Wiernick PH, et al: Hepatitis in patients with acute nonlymphocytic leukemia. Am J Med 75:413-422, 1983 54. Walters D, Robinson RG, Dick-Smith J B Poor response in two cases of juvenile rheumatoid arthritis to treatment with cyclophosphamide. Med J Aust 2:1070, 1972 55. Weber BL, Tanyer G, Poplack DG: Transient acute hepatotoxicity of high-dose methotrexate therapy during childhood. NCI Monogr 5:207-212, 1987 56. Weiss RB: Miscellaneous Toxicities. Philadelphia, Lippincott-Raven, 1997, pp 2796-2806 57. Zachariae H, Kragballe K, Sogaard H Methotrexate-induced cirrhosis. Br J Dermatol 102:407, 1980
Address reprint requests to John S. Macdonald, MD St. Vincents Comprehensive Cancer Center 111 Eighth Avenue Suite 1513 New York, NY 10011 e-mail: [email protected]
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CANCER CHEMOTHERAPY AND THE LIVER John S. Macdonald, MD
The clinical issues involved in potential hepatotoxicity from cancer chemotherapy may be complex because it is sometimes difficult to assess the cause and effect relationship between the administration of chemotherapeutic agents and hepatic abn~rmalities.~~ Patients with cancer frequently have a variety of reasons for liver abnormalities. In patients with solid tumors, the liver is a common site of metastasis, and the liver metastases will produce abnormal liver function studies and eventually hepatic failure. Also, many patients with malignant disease require frequent blood and blood-product transfusions, particularly in patients with hematologic malignancies. Such patients may develop transfusion-associated viral hepatitis-produced liver abnormalities," which may be difficult to separate from the potential toxic effects of chemotherapeutic agents. Finally, most patients with cancer are being treated with a variety of noncytotoxic drugs. They may be receiving antiemetics, analgesics and antibiotics, all of which may produce hepatic abnormalities. Although the attribution of specific liver abnormalities to specific chemotherapeutic drugs may sometimes be complex and problematical, there is no question that a number of commonly used chemotherapy drugs are associated with hepatotoxi~ity.~~ The clinician managing patients with cancer should have an understanding of the drugs that are commonly associated with hepatotoxicity, whether that hepatotoxicity is reversible, and whether it is predictable or idiosyncratic in nature. Clinicians must also be aware that the potential for hepatotoxicity with chemotherapeutic drugs in many instances may be dose related. AlFrom the Gastrointestinal Oncology Service, St. Vincents Comprehensive Cancer Center, New York, New York
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though this latter statement seems self-evident, it is a progressively important consideration now considering the widespread use of highdose chemotherapy, with stem-cell support in both hematologic and nonhematologic malignancies. This article discusses some of the more important commercially available drugs that may cause hepatotoxicity, the severity of such hepatotoxicity, and the prevention or management of drug-induced hepatotoxicity where that information is known. It also discusses the interaction of high (bone marrow transplant)-dose chemotherapy and liver function, and the need to modify dose and schedule of chemotherapeutic drugs in patients with pre-existing liver function abnormalities. WIDELY AVAILABLE DRUGS KNOWN TO CAUSE HEPATOTOXICITY
Drugs that commonly produce hepatotoxicity are L-asparaginase, methotrexate, cytarabine, 6-Thiopurines, and mithramycin. L-asparaginase
L-asparaginase is an enzyme used predominantly in the therapy of acute lymphocytic leukemia. It is an important component of the modern combination chemotherapy of leukemia in children. L-asparaginase functions by serving as an enzyme producing the hydrolysis of asparagine to aspartic acid and ammonia. The drug appears to function as a potent inhibitor of protein synthesis, presumably by causing a decrease in asparagine, a nonessential amino acid.* L-asparaginase has several major toxicities. These include hypersensitivity, which is a common toxicity and appears to be the result of the production of antibodies by the patient against L-asparaginase, which is a bacterial protein. Another major toxicity is pancreatitis, which occurs in approximately 50% of cases.8L-asparaginase also can produce hepatotoxicity. The hepatic toxicity of L-asparaginase is both indirect and direct. The indirect hepatotoxicity is a result of the inhibition of protein ~ynthesis.~ Inhibition of hepatic protein synthesis results in a decrease in albumin production with resultant hypoalbuminemia, but also decreases the synthesis of clotting factors and antithrombotic factors, such as Antithrombin-I11 and proteins C and S. The result of this may be the occurrence of both thrombotic and hemorrhagic complications in patients receiving L-asparaginase. The direct hepatotoxicity of L-asparaginase results in elevations of transaminases, alkaline phosphatase and bilirubin. When a liver biopsy is performed, fatty infiltration of the liver is frequently seen. Asparaginase does not appear to produce permanent hepatotoxicity, and when drug therapy is discontinued, liver function tests normalize. Chronic fibrosis and cirrhosis do not occur. Abnormal liver function tests will
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occur in close to 100% of patients receiving L-asparaginase for the therapy of leukemia. It is probable that hepatic steatosis is caused by decreased mobilization of lipids from the liver.6Whether this is a direct result of inhibition of the synthesis of enzymes important for hepatic lipid homeostasis is unknown.
Methotrexate Methotrexate is an antimetabolite that is a potent inhibitor of the enzyme dihydrofolate reductase. Methotrexate is one of the oldest chemotherapeutic agents in the armamentarium of the oncologist. This drug has been used for the last 45 years in the treatment of a number of malignancies including leukemias, particularly childhood leukemia, and a variety of solid tumors, including head and neck cancers, pediatric tumors and sarcomas. It has been used in both conventional dose and high-dose schedules. The qualitative toxicities' reproducibly associated with methotrexate are familiar to oncologists. Methotrexate may be given by a variety of routes including oral, subcutaneous, intramuscular, and intravenous schedules. The drug is routinely associated with myelosuppression and mucositis in conventional dosing schedules. In higher doses, methotrexate may cause nephrotoxicity, which may be a direct effect of precipitation of the drug in renal tubules.' Vigorous hydration and alkalization of the urine may avoid this toxicity. The toxicity of methotrexate is ameliorated by the administration of the tetrahydrofolate folinic acid (leukovorin),which is the product of the reaction catalyzed by dihydrofolate reductase. Methotrexate may also produce hepatotoxicity. Reversible elevations in bilirubin and transaminases are not uncommon in patients receiving high-dose methotrexate with leukovorin rescue. These findings primarily are clinical chemistry abnormalities and are not associated with longterm hepatic sequelae.' Liver biopsy may demonstrate fatty change but no fibrosis or cirrhosis.55There is strong evidence57that longterm, daily, oral administration of methotrexate (a dose and schedule used in the past in acute childhood leukemia or in the treatment of nonmalignant diseases such as psoriasis and arthritis) may be associated with the development of chronic fibrosis leading to clinical manifestation of heAs many as 25% of patients with chronic daily oral patic ~irrh0sis.l~ administration methotrexate will develop hepatic fibrosis.57Hepatotoxicity also appears to be more common in patients receiving methotrexate who have some degree of underlying chronic liver disease, typically as a result of alcohol abuse.I3The mechanism of hepatic injury leading to fibrosis/cirrhosis in methotrexate-induced liver injury is not clear. The likelihood of this toxicity can be markedly decreased or essentially eliminated by using intermittent forms of therapy rather than daily oral schedules of treatment.
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Cytarabine Cytarabine or Ara-C is a deoxycytidine analogue5 widely used in the treatment of acute leukemias. In the induction regimens for acute leukemia, ara-C is used frequently in continuous infusion regimens of 100 to 200 mg/m2/day for 7 days. The drug may be used in conventional-dose schedules or in high-dose schedules (2 to 3 gm/m2 every 12 hours) in both induction and consolidation regimens for acute myelogenous leukemia. The mechanism of action of ara-C requires in vivo phosphorylation of the drug to the triphosphate ara-CTP. Ara-CTP may then be incorporated into DNA as a false nucleotide in place of deoxycytidine triphosphate, resulting in inhibition of DNA polymera~es.’~ The major dose-limiting toxicity of ara-C is myelosuppression. At the standard doses of 100 to 200 mg/m2/d given by continuous infusion over 7-day periods, myelosuppression with leukopenia and thrombocytopenia are always seen. Higher doses of ara-C, typically 2 to 3 g/m2 every 12 hours, also produce significant myelosuppression and gastrointestinal toxicity. Neurologic toxicity also may be produced by high-dose a~a-C.~ Liver function abnormalities are commonly seen with ara-CZ3,46 In the continuous low-dose regimens, liver function abnormalities are manifested by moderate elevation of transaminases with mild jaundice. It is uncommon for liver function abnormalities to require interruption or attenuation of high-dose ara-C therapy; however, cholestatic jaundice and elevation of transaminases are common, and reports of liver biopsy performed in patients with liver abnormalities after receiving ara-C demonstrate intrahepatic cholestasis.20Hepatic function abnormalities produced by cytosine arabinoside are reversible. The mechanisms of hepatotoxicity with ara-C are not defined, but it is thought that the drug inhibits transport mechanisms in the hepatocytes. Although as many as 85% to 90% of patients receiving high-dose ara-C may develop abnormal liver function tests,16 this toxicity essentially is always reversible and does not preclude further treatment with ara-C.35,46 6-Thiopurines The 6-thiopurines as represented by the clinically useful drugs 6mercaptopurine (6-MP) and 6-thioguanine (6-TG)are used in the therapy of acute leukemia.18,28 Azathioprine, another drug in this class, is an analogue of 6-MP and is used primarily as an immuno~uppressive.~~ Azathioprine is rapidly metabolized to 6-MP in vivo. Both 6-MP and 6TG inhibit de novo purine synthesis and also inhibit purine interconversions. When anabolized to the triphosphate or nucleotide forms, the thiopurines may be incorporated into nucleic acids. The major toxicity of 6-MP is myelosuppression, but gastrointestinal toxicities, such as stomatitis, diarrhea, and vomiting, are also common. Hepatotoxicity also is commonly seen with 6-MP. As many as 30%
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of patients may develop hepatotoxicity manifested as cholestatic jaundice with or without elevations of hepatic transamina~es.'~ These liver abnormalities typically are more of a laboratory phenomenon than a significant clinical event and are reversible when the drug is stopped. When liver biopsies are performed, it is uncommon to see any significant hepatic necrosis and, typically, mild intrahepatic cholestasis is the major abnormality observed. There also may be some hepatocyte atypia noted.37Because such a relatively large proportion of patients receiving 6-MP develop chemical manifestations of hepatotoxicity, it is important not to administer 6-MP with other known hepatotoxic agents. 6-TG has rarely been associated with liver toxicity, particularly when compared with the relatively frequent hepatic abnormalities seen with 6-MP. If 6-TG is related to hepatic toxicity, the association appears to be an idiosyncratic one. 6-TG has been associated with a single case of peliosis hepatica and also has been noted in case reports to be possibly implicated as a cause of hepatic veno-occlusive disease (VOD).21,36
Mithramycin (Plicamycin)
Mithramycin is an antineoplastic antibiotic that is rarely used for antineoplastic therapy at present, although it does have activity against embryonal cell carcinoma of the testes.33The drug, which is a potent inhibitor of DNA-directed RNA synthesis, now is used mainly in the 47 Mithramycin therapy of hypercalcemia associated with malignan~y.'~, is one of the most potent hepatotoxins ever used in the therapy of cancer. When used in therapeutic doses for testicular cancer, mithramycin was associated with very significant transaminase elevation in essentially 100% of patients. The drug also has a secondary hepatic toxicity in that it is a very potent inhibitor of nucleic acid synthesis, which leads to decreased protein synthesis, causing a rapid decrease in levels of coagulation factors 11, V, VII, and X and a resultant significant coagulopathy. Hemorrhagic complications as a result of this coagulopathy were freq ~ e n t The . ~ ~ significant hepatotoxicity and coagulopathies associated with Mithramycin therapy clearly are dose-related. When fiithramycin is used in the relatively low-dose of 25 kg/kg as a single intravenous injection in the treatment of hypercalcemia, coagulopathy is extremely rare, and mild reversible enzyme elevation is noted in less than 20% of cases."
NEW AGENTS
Two major classes of recently developed chemotherapeutic agents are being widely evaluated in the therapy of cancer. These include the taxanes as characterized by tax01~~ and taxotere,52and the topoisomerase1 inhibitors as represented by t ~ p o t e c a nand ~ ~ CPT-11.50These drugs are
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being widely evaluated and have significant roles in the treatment of breast cancer, ovarian cancer, lung cancer, and gastrointestinal cancers. Both the topoisomerase-1 inhibitors and the taxanes are plant-derived natural products. These drugs vary in their dependence upon hepatic metabolism, but the liver is important in the metabolism of ta~anes,2~ and CPT-11.27The taxanes and the topoisomerase-1 inhibitors are not associated with significant liver toxicity in clinically used doses and schedules; however, docetaxel (taxotere) frequently produces accumulation of fluid into third spaces. This is not hepatic toxicity, but may produce ascites that could be confused with hepatic decompensation in patients with advanced cancer.52 HIGH-DOSE CHEMOTHERAPY
With the widespread use of the clinical strategy of bone marrow transplantation or peripheral blood stem cell support of high-dose chemotherapy, hepatotoxicity resulting from high doses of chemotherapy has been a finding of increasing clinical importance. Drugs commonly used in high doses with bone marrow or stem cell transplant and associated with VOD Busalfan Cyclophosphamide Etoposide Cyclophosphamide is an alkylating agent that requires conversion by hepatic microsomal enzymes to an active alkylating moiety 4-OH cyclophosphamide. Although hepatic metabolism is an important aspect of the clinical pharmacology of cyclophosphamide, the drug is not intrinsically hepatotoxic. It has only rarely been reported to be associated with liver function test abnormalities. When this occurs, it is probably secondary to an idiosyncratic rea~tion.~,54 Busulfan is an alkylating agent that is no longer commonly used in conventional doses. In the past, before the effectiveness of a-interferon and hydroxyurea were documented for the treatment of chronic myelogenous leukemia and other myeloproliferative syndromes, busulfan was commonly used in low-dose oral schedules. Hepatic dysfunction with this drug used in low doses was unc0mmon.3~In high doses, busulfan may be associated with an important hepatotoxicity, hepatic VOD.34 The third commonly used high-dose chemotherapy agent is the topoisomerase-2 inhibitor, etoposide. This natural product is excreted primarily in the bile and, in conventional doses, is not considered to be hepatotoxic.3°In higher doses used as a single agenP and in combination with cytosine arabinoside,’O the drug has been associated with abnormalities in liver function, including elevation of transaminases and alkaline phosphatase. These abnormalities reversed after completion of chemotherapy and were not associated with long-term hepatic abnormalities or chronic fibrosis/cirrhosis.
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Although cyclophosphamide, busulfan, and etoposide are of low intrinsic hepatotoxicity, a major complication of bone marrow transplant that may be fatal, hepatic VOD, is likely associated with the use of highdose chemotherapy used in the transplant setting.41VOD results from obstruction or thrombosis in the postcapillary hepatic venules. Clinical manifestations of VOD are the sudden onset of right upper quadrant pain, hepatomegaly, and the rapid development of transudative ascites secondary to hepatic postsinusoidal obstruction and increased portal pressure. Liver function abnormalities rapidly develop and are indicated by elevations in hepatic enzymes and bilirubin. The clinical manifestations of hepatic VOD are essentially identical to those of the Budd-Chiari syndrome, developing as a result of hepatic vein thrombosis. It appears that VOD in the setting of transplantation is the result of damage to hepatic venule endothelial surfaces by cytotoxic therapy and probably not primarily caused by the induction of hepatic vein or venule thrombosk41 The overall incidence of VOD in the setting of bone marrow transplant is relatively high and approaches 20%32,41 VOD of the liver following bone marrow transplant. VOD is fatal in more than 50% of cases. It is not known why particular patients develop VOD post-transplant, but VOD does appear to be associated with drugs that require metabolism in the liver.34It also may be more common in patients who have underlying hepatic abnormalities either induced by previous conventional chemotherapy, concurrent hepatitis, or significant metastatic disease in the liver. Busulfan in particular, which is typically given at doses of 4 mg/kg/d for 4 consecutive days in pretransplant regimens, has been associated with the production of VOD in patients with acute leukemia. In some series, approximately 20% of patients receiving busulfan at this dose and schedule develop some manifestations of VOD.25The therapy of VOD is unsatisfactory and essentially supportive. Rapidly progressive hepatic failure implies a poor prognosis, whereas patients with relatively stable liver function abnormalities whose ascites respond to diuretics generally will survive VOD. DOSE MODIFICATION AND HEPATIC FUNCTION
The effect of abnormal hepatic function upon the clinical pharmacology of antineoplastic agents may be important clinically in planning the dosage and schedule of chemotherapy. The assessment of need for dose modification of chemotherapeutic agents in patients with abnormal hepatic function is an important clinical issue. Many cancer chemotherapeutic drugs depend on hepatic metabolism, at least in part. Both the clinical beneficial effect, that is cancer cell cytotoxicity, and the toxic effects of cancer chemotherapeutic agents, generally depend upon the product of the plasma drug concentration multiplied by the time of drug exposure (C X T) achieved by a particular dose and schedule. Therefore, changes in hepatic function as they affect drug metabolism and clearance
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may alter both the antineoplastic effect and the toxicity patterns seen with cancer chemotherapy. There are a number of drugs commonly used, including anthracyclines, vinca alkaloids, epipodophyllotoxins, taxanes, and some topoisomerase-1 inhibitors, which undergo either hepatic metabolism or biliary clearance. Dose modification in patients with altered hepatic function is an important clinical issue in patients treated with these drugs. Drugs that may require dose modification in cases of abnormal hepatic function Anthracyclines Doxorubicin Daunorubicin Idarubicin Epipodophyllotoxins Etoposide Teniposide Topoisomerase-I inhibitors CPT-11 Vincas Vincristine Vinblastine Vinorelbine Vindesine Taxanes Docetaxel Paclitaxel The anthracyclines (idarubicin, doxorubicin, and daunorubicin) are metabolized significantly in the liver. Renal clearance of these drugs is a very minor factor in their clinical pharmacology and it is not necessary to modify doses of anthracyclines secondary to renal insuffi~iency.~ Unfortunately, with regard to hepatic function abnormalities, there are not adequate data to give clear clinical guidelines as to the need for dose modification of anthracyclines therapy. Generally, 50% reductions of drug are considered when the bilirubin is between 1.5 and 3.0 mg/dL or when transaminases are less than 3 times the upper limit of normal. When the bilirubin is between 3.1 and 5 mg/dL or the transaminases exceed 3 times the upper limit of normal, 50% to 25% of projected dose is recommended. If bilirubin is greater than 5 mg/dL, omission of the anthracycline therapy may be required; however, these rough guidelines must be taken in the context of the potential clinical benefit to the patient from administration of anthracyclines. There is some evidence that administration of full doses of doxorubicin in the face of abnormal liver function tests can be done safely without significantly increased drug If the patient has a malignancy likely to respond well to anthracycline, one may reasonably give h l l doses of therapy with abnormal liver function, with the understanding that toxicity may be increased, but the clinical benefit may justify the increase in toxicity.
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This strategy is a particularly valid approach if one is treating hepatic metastases that have caused the liver function abnormalities. The vinca alkaloids are commonly used drugs that are metabolized in the liver. Less than 50% of administered doses of vincristine, vinblastine, vindesine, and navelbine, are excreted in the urine.15Because of the magnitude of hepatic metabolism of the vincas, there is appropriate concern that in patients with abnormal liver function the toxicity of these drugs may be increased. As with anthracycline, there are no good data showing a clear relationship between abnormal liver function tests and plasma levels of vinca alkaloids; however, the toxicity of vincas appears to increase when they are administered in patients with hyperbilir~binemia.~~ Many oncologists, therefore, omit therapy with vinca alkaloids in patients with bilirubin levels greater than 3.0 mg/dL. The epipodophyllotoxins, as represented clinically in adult oncology by etoposide, have a somewhat different metabolism than the vinca alka10ids.I~Metabolism, most likely hepatic metabolism, of etoposide is an important mechanism of drug clearance, along with renal clearance of unmetabolized drug. Approximately 50% of intravenously administered etoposide is excreted in the urine.12Although approximately 50% of the metabolism of etoposide at most is dependent on the liver, there is still concern about administering this drug in patients with significant liver abnormalities. This is because plasma etoposide is highly protein-bound. In patients with hyperbilirubinemia there is substantial displacement of bound etoposide by elevated plasma bilirubin. This effectively increases the free or clinically active etoposide plasma levels and may result in significant toxi~ity.'~, 48 Therefore, in patients with significant hyperbilirubinemia (> 5 mg/dL), etoposide is frequently omitted, and the dose may be modified to 75% of projected dose if the bilirubin is between 3 and 5 mg/dL. Paclitaxel is extensively metabolized in the liver, and biliary excretion of drug metabolites is important. There are data suggesting that patients with hyperbilirubinemia or increased hepatic transaminase levels are more likely to have toxic effects from Taxol than patients with normal liver function.51It appears appropriate to decrease the dose of Taxol by 50% in patients with significant liver abnormalities (bilirubin 2 3 mg/dL or transaminases 2 3 times normal). As with paclitaxel, docetaxel is also extensively metabolized in the liver, and patients with significant liver function abnormalities (alkaline phosphatase > 2.5 times normal, transaminases > 1.5 times normal) should have a minimum of 25% dose reduction.43 Gastrointestinal toxicity from CPT-11 has an interesting relationship with hepatic metabolism. The major clinical toxicity of CPT-11 is diarrhea. To be active as an antineoplastic agent, CPT-11 must be metabolized to its active form, SN-38, by carboxylesterase. This metabolism to SN-38 may occur intracellularly in colon cancer cells. A potential mechanism of resistance to CPT-11 is decreased production of SN-3€L40SN-38 is conjugated in the liver to its glucuronide, and decreased hepatic metabolism of SN-38 may lead to an increased incidence of diarrhea in patients
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receiving CPT-11. It is assumed that unconjugated SN-38 excreted in the bile is toxic to the mucosa of the bowel and causes diarrhea.26Another area of interest with regard to hepatic function and CPT-11 concerns patients with Gilbert’s syndrome. These patients may be more sensitive to CPT-11 toxicity. It is probable that the decreased hepatic production of the SN-38 glucuronide occurs in Gilbert’s cases and results in increased CPT-11 toxicity. The Gilbert’s association presently is only a clinical observation. More information bearing upon a possible association between Gilbert’s syndrome and CPT-11 bowel toxicity will have to be obtained before this relationship may be confirmed. ACKNOWLEDGMENT The author greatly acknowledges the expert technical assistance of John Bazos in preparing this manuscript.
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47. Slayton RE, Shnider B, Eliase E: New approach to the treatment of hypercalcemia: The effect of short term treatment with mithramycin. Clin Pharmacol Ther 12:833-837,1971 48. Stewart CF, Arbuck SG, Fleming RA: Changes in the clearance of total and unbound etoposide in patients with liver dysfunction. J Clin Oncol 8:1874-1879, 1990 49. Sulkes A, Collins J M Reappraisal of some dosage adjustment guidelines. Cancer Treat Rep 71:229-233, 1997 50. Tanizawa A, Fujimori A, Fujimori Y, et al: Comparison of topoisomerase I inhibition, DNA damage, and cytotoxicity of camptothecin derivatives presently in clinical trials. J Natl Cancer Inst 86:836, 1994 51. Venock AP, Egorin M, Braun TD: Paclitaxel (Taxol) in patients with liver dysfunction (CALGB 9264) (Abstract). Proc Am SOC Clin Oncol 13139, 1994 52. Verweij J, Clavel M, Chevalier 8: Paclitaxel (Taxol) and docetaxel (Taxotere): Not simply two of a kind. Ann Oncol5:495, 1994 53. Wade JC, Gaffey M, Wiernick PH, et al: Hepatitis in patients with acute nonlymphocytic leukemia. Am J Med 75:413-422, 1983 54. Walters D, Robinson RG, Dick-Smith J B Poor response in two cases of juvenile rheumatoid arthritis to treatment with cyclophosphamide. Med J Aust 2:1070, 1972 55. Weber BL, Tanyer G, Poplack DG: Transient acute hepatotoxicity of high-dose methotrexate therapy during childhood. NCI Monogr 5:207-212, 1987 56. Weiss RB: Miscellaneous Toxicities. Philadelphia, Lippincott-Raven, 1997, pp 2796-2806 57. Zachariae H, Kragballe K, Sogaard H Methotrexate-induced cirrhosis. Br J Dermatol 102:407, 1980
Address reprint requests to John S. Macdonald, MD St. Vincents Comprehensive Cancer Center 111 Eighth Avenue Suite 1513 New York, NY 10011 e-mail: [email protected]