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Cancer Chemotherapy II: Atypical Hepatic Injuries
Clin Liver Dis 11 (2007) 663–676
Cancer Chemotherapy II: Atypical Hepatic Injuries Edmundo A. Rodriguez-Frias, MDa, William M. Lee, MDb,* a
Department of Internal Medicine, The University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, Texas 75390, USA b Division of Digestive and Liver Diseases, The University of Texas Southwestern Medical Center at Dallas, 5959 Harry Hines Boulevard, HP-4.420, Dallas, Texas 75390-8887, USA
Although chemotherapy generally is accompanied by regular testing for liver enzyme abnormalities, atypical reactions may occur that escape ordinary detection, because hepatocyte injury is not the primary event. The presence of fatty liver, mitochondrial changes, and even biliary abnormalities can be associated with normal or nearly normal liver enzyme levels. Nonetheless, the liver is enduring ongoing damage, and an extra level of alertness is appropriate, particularly with drugs associated more frequently with these unusual hepatic reactions.
Hypersensitivity Eosinophilia, although traditionally associated with drug reactions, is quite infrequent in hepatocyte injury settings. Specific examples are rare among oncologic drugs. Dacarbazine, widely used for treatment of malignant melanoma, has been associated with a few cases of fatal liver failure. Liver biopsies have shown evidence of veno-occlusive (VOD) disease and striking eosinophilic infiltrates, suggesting an association with hypersensitivity reaction [1,2]. There have been case reports of an azathioprine-related hypersensitivity reaction that is thought to be secondary to an IgE mediated response [3]. Few other instances of true immunoallergic reactions have been reported with chemotherapeutic drugs. In the present era most reactions are associated with anti-epileptic drugs, phenytoin being the principal culprit.
* Corresponding author. E-mail address: [email protected] (W.M. Lee). 1089-3261/07/$ - see front matter Ó 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.cld.2007.06.012 liver.theclinics.com
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Cholestasis Cholestasis, obstruction to bile flow, seldom leads to liver failure but can do so in a long, indolent illness characterized by permanent bile duct injury. Relatively pure cholestatic reactions are associated with lower aminotransferase levels and more elevated alkaline phosphatase and bilirubin levels. The classic definition of cholestasis requires that the alkaline phosphatase value be more than five times the upper limit of normal and the aminotransferase levels less than two times the upper limit of normal . On biopsy, it is difficult to identify any remaining bile ducts within the portal tracts. Death results from prolonged, low-grade, systemic illness with inanition, usually in the elderly. Busulfan is rarely used for myeloproliferative disorders and is cleared quickly from the blood and excreted in urine. Liver metabolism is not relevant. It has been reported as a cause of cholestatic jaundice in two isolated cases, although one patient also had leukemic infiltration of the liver [4,5]. Chlorambucil produced cholestasis findings on autopsy in 6 of 181 patients in one series. Damage usually was seen in central areas but occasionally was midzonal or periportal [6]. Cyclophosphamide-induced hepatotoxicity usually has been reported in patients taking high cumulative doses or in those treated for a long time [7–9]. There is a single case report of acute icteric hepatitis with evidence of cholestasis and cholangitic damage determined by liver biopsy in a patient treated with low-dose cyclophosphamide for a short time [10]. Gemcitabine is a fluorine analogue of cytarabine with broad-spectrum antitumor activity. It is used in the treatment of pancreatic cancer, often with hepatic metastases. Frequently, this drug produces transient transaminase elevation, but it also has been implicated in at least four cases of fatal cholestatic hepatotoxicity [11–14]. Pre-existing liver metastases and/or a bilirubin level higher than 1.6 mg/dL at onset of treatment are considered definite risk factors for developing liver failure [15,16]. 6-Mercaptopurine is used in acute lymphocytic leukemia. It produces cholestatic injury more frequently in adults than in children. Jaundice and elevation of aspartate aminotransferase appear after 1 or 2 months of treatment and are reversible after discontinuation of the drug. Hepatic necrosis was found in rats [17–19]. There is a case report of cholestatic liver failure in association with doxorubicin [20]. Azathioprine is related to mercaptopurine. It is been used in solid-organ transplantation and in the treatment of psoriasis, rheumatoid arthritis, inflammatory bowel disease, and autoimmune hepatitis. The incidence of liver toxicity is remarkably low when compared with mercaptopurine, but the clinical presentation is similar [21]. Liver biopsies at 6 and 24 months in patients who had psoriasis and taking high doses of azathioprine showed minimal evidence of cholestasis, which was reversible after cessation of the drug, in only a few cases [22].
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Cytarabine is used in lymphoma, acute myelogenous leukemia, and myelodysplastic syndrome. High doses predict disease-free survival. One study of patients who had leukemia treated with high doses showed liver abnormalities in about 40% of cases, although in many cases there were other explanations for these changes [23]. Dose-dependent hepatotoxicity has been seen with continuous, high-dose infusions for longer than 3 days [24]. A few case reports have linked hepatotoxicity with high doses of cytarabine, as seen by liver biopsy [25,26]. With a few exceptions, the liver damage follows a cholestatic jaundice pattern, usually mild and reversible [27,28].
Hepatic steatosis The accumulation of fat within liver cells takes two forms. Microvesicular fat present within hepatocytes causes cell swelling and dysfunction. Macrovesicular fat consists of large droplets that accumulate outside hepatocytes. Recent evidence suggests that cirrhosis can develop from the presence of fatty change over a short or long time interval [29]. Oxiloplatin and irinotecan used for preoperative chemotherapy before resective surgery of hepatic metastases have been associated with severe steatohepatitis, especially in obese patients. The findings have important implications, because these observations could limit the ability to perform large liver resections in patients who have undergone this particular chemotherapy for hepatic colorectal metastases. A liver biopsy to look the histology before surgery might alter the final management of these patients [30]. Tamoxifen is a selective estrogen receptor modulator used as adjuvant treatment in estrogen receptor–positive breast cancer. The most common pattern of injury is fatty liver, reported in up to 30% of cases [31], but progression to steatohepatitis and cirrhosis is said to be rare [32–36]. One study evaluated the use of tamoxifen in patients who had known pre-existing liver steatosis and found that 43% of these patients developed hepatotoxicity, especially if they had pre-existing obesity, diabetes, or higher lipid levels. Glucose intolerance was probably the most important predictive factor [37]. Tamoxifen is associated with a twofold-increased risk of developing steatohepatitis, especially in overweight women [38]. Leptin levels, which correlate with body fat mass, are increased in tamoxifen-induced steatosis [39]. Fatty liver normally appears as early as 3 months after beginning therapy and persists for more than 4 years after discontinuation. Therefore, long-term follow-up is warranted [40]. It also has been shown in several long-term studies to be hepatocarcinogenic in rats through activation of cytochrome P-450 (CYP450) to an electrophile that binds irreversibly to the DNA. Toremifene and raloxifene do not share this side effect [41–44]. Other forms of hepatotoxicity reported in addition to steatohepatitis include peliosis hepatis [45] and acute hepatitis [46]. The benefit of using tamoxifen
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in estrogen receptor–positive breast cancer for more than 5 years might outweigh the risk of adverse effects, but this issue remains controversial [47]. In a study of toremifene in breast cancer, 7.7% patients had fatty liver as shown by CT scan, a rate that is significantly lower than historical studies in patients treated with tamoxifen. Therefore, it is suggested that patients who receive an antiestrogen agent be screened annually for fatty liver by ultrasound [48]. Exemestane is a new aromatase inhibitor used in patients who have breast cancer. A study done in patients who had liver impairment showed no important side effect in its safety profile [49]. Stilbesterol was widely used for prostate cancer in the past; however, it has largely been replaced by newer agents with superior safety profiles [50]. Steatohepatitis has been seen in animal models [51] and in one case report of a patient who received treatment for 11 years, as proved by biopsy [52]. Veno-occlusive disease The use of high doses of cyclophosphamide as preparation for bone marrow transplantation is associated with hemorrhagic cystitis, pulmonary toxicity, cardiac necrosis, and VOD, defined as occlusion of hepatic venous outflow and thought to result from direct damage to venular endothelial cells. As discussed in other articles in this issue, cyclophosphamide is metabolized by CYP450 to form 4-hydroxy-cyclophosphamide and acrolein, which are unstable and decompose into phosphoramide mustard that is especially cytotoxic for the hepatic sinusoidal endothelial cells in zone 3 where the concentration of CYP450 is highest [53,54]. In rats, direct exposure of the sinusoids to cyclophosphamide itself did not provoke toxicity; however, when the sinusoidal endothelium is exposed to cyclophosphamide metabolites, a dose-dependent toxicity is observed that can be prevented with the use of serine-methionine that can raise the level of hepatocyte glutathione [55]. There is a known association between these two metabolites and the occurrence of VOD [56–58]. High doses of cyclophosphamide, alone or in combination with autologous bone marrow transplantation, have caused hepatic VOD in up to 50% of cases. Fulminant hepatic failure complicating severe VOD is associated with multiorgan failure and has a very poor prognosis [59,60]. The incidence of VOD could be reduced if the dose of cyclophosphamide were decreased, but this reduction might compromise efficacy as well. There are several reports of partial benefit with the use of N-acetyl cysteine in the treatment of VOD. Randomized clinical trials will need to be done to support this use of N-acetyl cysteine [61]. Gemcitabine has been associated with least to one case of VOD in the literature [62]. Acute liver failure caused by vascular occlusion in patients receiving dacarbazine as single-agent chemotherapy has been noted only rarely [63]. The liver failure has been ascribed to the depletion of glutathione [64].
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The use of azathioprine in renal transplant recipients may be closely linked with the development of VOD, and this disorder may be more common than previously reported. In these patients, serum bilirubin and alkaline phosphatase levels should be monitored closely for the earliest signs of VOD [65]. A follow-up of patients after bone marrow transplantation showed threeto fourfold increase of VOD in patients who had received busulfan [66]. Like cyclophosphamide, busulfan can deplete hepatic glutathione, predisposing the patient to further liver injury. Ursodiol is a hydrophilic, water-soluble bile acid; in some studies its action as antioxidant has been shown to impart a statistically significant protection [67,68], but other studies did not demonstrate any benefit [69]. In a few cases the use of oxaliplatin has been associated with sinusoidal obstruction, with fibrotic venular occlusion seen on liver biopsies [70]. Gemtuzumab combines a monoclonal antibody with a metabolic agent, calicheamicin, that is released inside the myeloid lysosome. It has been associated with some cases of VOD, with reported incidences as low as 2% [71] and as high as 21% [72] . The risk of post-gemtuzumab VOD probably is lower after autologous stem cell transplantation than after allogeneic stem cell transplantation and with longer intervals to transplantation [73]; VOD did not occur in patients treated with gemtuzumab more than 3.5 months before stem cell transplantation [72,74]. No specific demographic or disease-related risk factors have been associated with the development of VOD after the use of gemtuzumab [75]. One of eight patients who had acute myeloid leukemia and who relapsed after hematopoietic stem cell transplantation developed severe VOD and died 14 days after treatment with gemtuzumab [76]. Arceci and colleagues [77] found a higher incidence of VOD at dosages of 6 to 9 mg/m2 in children and in adults receiving stem cell transplantation. Daptinomycin is an inhibitor of transcription normally used in children who have nephroblastoma and rhabdomyosarcoma. It has been associated with VOD in up to 5% of cases, with the median duration of 27 days, and usually is self-limiting. One study suggested that amifostine could have a protective effect in those cases [78–80]. In general, the treatment for VOD is mainly supportive. Prevention of fatal VOD is a priority and in the case of busulfan can be achieved with pharmacokinetic monitoring of drug levels with the objective of minimizing further liver damage [81]. Different authors have used supplemental hepatic glutathione experimentally, because levels of glutathione and other antioxidants seem to decline after chemotherapy in the setting of transplantation. The results are still equivocal and anecdotal; further studies are in progress [82]. The most encouraging current treatment for VOD is defibrotide, which is believed to modulate endothelial cell injury and protect the sinusoidal endothelium. It has binding sites on adenosine receptors A1 and A2 (nucleotide
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receptors that participate in endothelial cell regulation). Defibrotide decreases thrombin generation, increases prostacyclin, and inhibits deposition of fibrin and collagen with subsequent reduction of fibrosis [83–87]. The earlier the intervention with defibrotide, the more effective is the outcome. The average active dose used was 25 mg/kg/d, with response to the treatment within the first 7 days [88].
Hepatic tumors associated with chemotherapy The use of drugs that promote anabolism in the setting of chronic wasting conditions such as HIV, burn injury, chronic diseases, and cancer has advanced the supportive care for cancer patients. At the regular dose of 20 mg/d, oxandrolone generally is better tolerated than other anabolic androgenic steroids. It did not show evidence of the hepatotoxic effects such as jaundice, cholestatic hepatitis, peliosis hepatis, hyperplasias, and neoplasms seen in the group of anabolic-androgenic steroids, because oxandrolone undergoes minimal hepatic metabolism and is excreted primarily in the urine [89–91]. At higher doses, cholestasis is a theoretical possibility but has not been identified [92]. Cyproterone acetate belongs to the family of progestins and is administered in prostate and breast cancer, severe acne, and other indications. It could produce a variety of hepatotoxic reactions including hepatocellular mutagenic potency leading to hepatocarcinogenesis [93–98]. In fact, this group of drugs is classified by the International Agency for Research on Cancer as possibly carcinogenic to humans [99]. The risk seems to be low when used at standard doses for the currently authorized indications, however [100]. Different studies have shown that cyproterone forms DNA adducts and elicits DNA repair in hepatocytes [101–103]. Lesions in DNA are indicated by the increase of the frequency of micronucleated cells, mutations, and enzyme-altered preneoplastic foci in liver of female rats, but the pathophysiology of its hepatotoxicity remains unclear [104]. There are a few reports of fatality linked to the use of cyproterone because of severe hepatitis, which is more common in elderly patients and after long treatment [105–108]. In most cases hepatotoxicity resolves with iscontinuation of the drug. In general, the latency before the onset of hepatocellular carcinoma is several years [109]. Clinical surveillance in patients who have pre-existing liver disease is encouraged. It is widely known that androgens can produce liver tumors, especially in patients who have Fanconi’s anemia [110,111]. Hepatocellular carcinoma in general is associated more often with the use of oxymetholone and methyltestosterone, whereas adenoma is associated more commonly with danazol. All patients taking anabolic androgenic steroids, regardless of underlying diagnosis, are at risk of liver tumors, and patients receiving long-term treatment should undergo routine screening by liver ultrasonography [112,113].
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Reactivation of viral hepatitis Ma and colleagues [114] reported a retrospective study in Chinese women who had breast cancer treated with doxorubicin and cyclophosphamide and compared their data with an historic Western cohort. Eight patients (9.4%) had hepatitis; five had mild hepatitis, and three had moderate-to-severe hepatitis. All were positive for hepatis B surface antigen (HbsAg), suggesting that reactivation of hepatis B virus was the culprit [114]. A number of series have emphasized that reactivation is observed most commonly in the setting of lymphoma but can occur with almost any chemotherapy and in various stages of hepatitis B infection [115,116]. Patients who have HBsAg positivity in serum and who are not pretreated with lamivudine before chemotherapy have more hepatotoxicity and hepatitis B reactivation [115,116]. The degree of reactivation ranges from mild hepatitis to fatal hepatic failure [115–119]. Different drugs (eg, imatinib) have been linked to fulminant hepatitis [120], and viral reactivation should be considered in all patients undergoing chemotherapy who have history of hepatitis B. It is advisable to screen all Asian patients and anyone who has risk factors for hepatitis B for active or inactive disease before initiating any form of significant chemo- or immunotherapy. Liver fibrosis Methotrexate is used for breast cancer, head and neck cancer, osteosarcoma, acute lymphocytic leukemia, and, in lower doses for psoriasis, inflammatory bowel disease, and rheumatoid arthritis. A study in patients who had psoriasis treated with methotrexate reported that regular monitoring of liver-associated enzymes did not correlate with histologic deterioration (findings on liver biopsy ranged from mild steatosis to severe fibrosis). The evaluators suggested that routine liver biopsies are necessary to monitor for methotrexate hepatotoxicity in this subset of patients [121]. Repeat liver biopsy has long been regarded as the only reliable method of detecting liver fibrosis, and it still is recommended by the American Academy of Dermatology. Serum procollagen III aminopeptide is formed during the synthesis of type III collagen and has been used as a marker for hepatic fibrosis in patients receiving long-term therapy with methotrexate. Although the test does not detect all instances of fibrosis, the risk of missing significant liver damage in patients who have persistently normal procollagen III aminopeptide is low. Serial measurements have been advocated as a means of reducing significantly the need for liver biopsy [122–124]. Summary The dose of anticancer drugs normally used is the highest that can be given to impact a therapeutic target with minimal probability of toxicity
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[125]. There are no clear guidelines on the use of anticancer drugs in patients who have liver impairment [126]. Liver impairment may not predispose a patient to increased toxicity but is likely to affect the degree of injury in certain settings [127]. Specifically, patients at higher risk of developing VOD are those who have underlying lymphoma, hepatic metastases, stem cell transplantation, prior radiation therapy, and receive a combination of drugs, especially cyclophosphamide and busulfan [81,128–130]. The most important risk factor for the development of VOD is pre-existing liver disease, particularly elevated alanine aminotransferase levels [131]. Serum bilirubin levels and weight gain are predictors of outcome. Unfortunately the treatment for VOD is mostly supportive, because several medications evaluated for prevention have not been scrutinized in large, well-randomized, valid studies [132]. In general, many of the anticancer drugs are used intravenously, so there are few studies that relate to their oral bioavailability or hepatic excretion [133]. Therapeutic monitoring may help prevent overdose and subsequent risk for potentially life-threatening toxicity. The development of pharmacogenomic tools to individualize treatment [134] may allow better drug targeting based on the specific genetic profile of the host and possibly of the tumor [135] and may help keep dangerous side effects from happening. Chemotherapeutic agents may cause different toxicities, including hepatotoxicity, especially in patients who have baseline liver impairment. Clinical judgment is important and relies on early detection and treatment of liver injury and prompt drug withdrawal if indicated. Better guidelines, pharmacokinetic studies, and reports of cases are needed to minimize hepatotoxicity in cancer chemotherapy.
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[58] Ren S, Slattery JT. Inhibition of carboxyethylphosphoramide mustard formation from 4-hydroxycyclophosphamide by carmustine. AAPS PharmSci 1999;1(3):E14. [59] Huitema AD, Spaander M, Mathjt RA, et al. Relationship between exposure and toxicity in high-dose chemotherapy with cyclophosphamide, thioTEPA and carboplatin. Ann Oncol 2002;13:374–84. [60] Antman K, Eder JP, Elias A, et al. High dose combination alkylating agent preparative regimen with autologous bone marrow support: the Dana-Farber Cancer Institute/Beth Israel Hospital experience. Cancer Treat Rep 1987;71:119–25. [61] MacQuillan GC, Mutimer D. Fulminant liver failure due to severe veno-occlusive disease after haematopoietic cell transplantation: a depressing experience. QJM 2004;97(9): 581–9. [62] Ringden O, Remberger M, Lehman S, et al. N-acetylcysteine for hepatic veno-occlusive disease after allogeneic stem cell transplantation. Bone Marrow Transplant 2000;25: 993–6. [63] Venook A, Egorin M, Rosner G. Phase I and pharmacokinetic trial of gemcitabine in patients with hepatic or renal dysfunction. Cancer and leukemia group B 9565. J Clin Oncol 2000;18(14):2780–7. [64] Greenstone MA, Dowd PM, Mikhailidis DP, et al. Hepatic vascular lesions associated with dacarbazine treatment. Br Med J 1981;282(6278):1744–5. [65] Katzka DA, Saul SH, Jorkasky D, et al. Azathioprine and hepatic venoocclusive disease in renal transplant patients. Gastroenterology 1986;90:446–54. [66] Shulman HM, McDonald GB, Matthews D, et al. An analysis of hepatic venocclusive disease and centrilobular hepatic degeneration following bone marrow transplantation. Gastroenterology 1980;79:1178–91. [67] Ohashi K, Tanabe J, Watanabe R, et al. The Japanese multicenter open randomized trial of ursodeoxycholic acid prophylaxis for hepatic veno-occlusive disease after stem cell transplantation. Am J Hematol 2000;64:32–8. [68] Essell JH, Schroeder MT, Harman GS, et al. Ursodiol prophylaxis against hepatic complications of allogeneic bone marrow transplantation. A randomized, double-blind, placebocontrolled trial. Ann Intern Med 1998;128:975–81. [69] Ruutu T, Eriksson B, Remes K, et al. Ursodiol prevention of hepatic complications in allogeneic stem cell transplantation: results of a prospective, randomized, placebo-controlled trial. Bone Marrow Transplant 1999;23:756. [70] Rubbia-Brandt L, Audar V. Severe hepatic sinusoidal obstruction associated with oxaliplatin-based chemotherapy in patients with metastatic colorectal cancer. Ann Oncol 2004;15: 460–6. [71] Nabhan C, Rundhaugen L, Jatoi M, et al. Gemtuzumab ozogamicin (MylotargTM) is infrequently associated with sinusoidal obstructive syndrome/veno-occlusive disease. Ann Oncol 2004;15(8):1231–6. [72] Wadleigh M, Richardson PG, Zahrieh D, et al. Prior gemtuzumab ozogamicin exposure significantly increases the risk of veno-occlusive disease in patients who undergo myeloablative allogeneic stem cell transplantation. Blood 2003;102(5):1578–82. [73] Sievers EL, Spielberger R, Brunvand MW, et al. Gemtuzumab ozogamicin (Mylotarg) as a single agent to evaluate safety and determine maximum tolerated dose in post hemopoietic stem cell transplant patients with relapsed, CD 33þ acute myeloid leukemia. Blood 2002;100(11):336. [74] Erba HP, Stadtmauer EA, Larson RA, et al. Risk assessment for hepatic veno-occlusive disease in patients treated with gemtuzumab ozogamicin (Mylotarg) with or without hematopoietic stem cell transplantation [abstract no 3241]. Blood 2003;102:871a. [75] Erba HP, Stadtmauer EA, Larson RA, et al. Final results of a multivariate logistic regression analysis to determine factors contributing to the risk of developing hepatic veno-occlusive disease after treatment with gemtuzumab ozogamicin [abstract no 1313]. Blood 2002; 100:339a.
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[76] Cohen AD, Luger SM, Sickles C, et al. Gemtuzumab ozogamicin (Mylotarg) monotherapy for relapsed AML after hematopoietic stem cell transplant: efficacy and incidence of hepatic veno-occlusive disease. Bone Marrow Transplant 2002;30:23–8. [77] Arceci RJ, Sande J, Lange B, et al. Safety and efficacy of gemtuzumab ozogamicin (Mylotarg) in pediatric patients with advanced CD33-positive acute myeloid leukemia. Blood 2005;106(4):1183–8. [78] Czauderna P, Katski K, Kowalczyk J, et al. Venoocclusive liver disease (VOD) as a complication of Wilms’ tumor management in the series of consecutive 206 patients. Eur J Pediatr Surg 2000;10(5):300–3. [79] Sulis ML, Bessmertny O, Granowetter L, et al. Veno-occlusive disease in pediatric patients receiving actinomycin D and vincristine only for the treatment of rhabdomyosarcoma. J Pediatr Hematol Oncol 2004;26(12):843–6. [80] Czauderna P, Chyczewski L, Lech K, et al. Experimental model of hepatic venoocclusive disease (VOD) caused by dactinomycin-D preliminary report about hepatoprotective effect of amifostine. Med Sci Monit 2000;6(3):446–53. [81] Wadleigh M, Ho V, Momtaz P, et al. Hepatic veno-occlusive disease: pathogenesis, diagnosis and treatment. Curr Opin Hematol 2003;10:451–62. [82] Goringe AP, Brown S, O’Callaghan U, et al. Glutamine and vitamin E in the treatment of hepatic veno-occlusive disease following high-dose chemotherapy. Bone Marrow Transplant 1998;21:829–32. [83] Bianchi G, Barone D, Lanzarotti E, et al. Defibrotide, a single-stranded polydeoxyribonucleotide acting as an adenosine receptor agonist. Eur J Pharmacol 1993;238:327–34. [84] Berti F, Rossoni G, Biasi G, et al. Defibrotide by enhancing prostacyclin generation prevents endothelin-I induced contraction in human saphenous veins. Prostaglandins 1990; 40:337–50. [85] Coccheri S, Biagi G, Legnani C, et al. Acute effects of defibrotide, an experimental antithrombotic agent, on fibrinolysis and blood prostanoids in man. Eur J Clin Pharmacol 1988; 3:151–6. [86] Ulutin ON. Antithrombotic effect and clinical potential of defibrotide. Semin Thromb Hemost 1993;19:186–91. [87] Chalandon Y, Roosnek E, Helg C, et al. Efficient prophylaxis with defibrotide for hepatic veno-occlusive disease after allogeneic stem cell transplantation. Blood 2002;100:111. [88] Chopra R, Eaton JS, Grassi A, et al. Defibrotide for the treatment of hepatic venoocclusive disease: results of the European compassionate-use study. Br J Haematol 2000; 111:1122–9. [89] Orr R, Fiatarone S. The anabolic androgenic steroid oxandrolone in the treatment of wasting and catabolic disorders: review of efficacy and safety. Drugs 2004;64(7):725–50. [90] Boughton B. Drug increases lean tissue mass in patients with cancer. Lancet Oncol 2003; 4(3):135. [91] Karim A, Ranney RE, Zagarella J, et al. Oxandrolone disposition and metabolism in man. Clin Pharmacol Ther 1973;14:862–9. [92] Langer C, Hoffman JP, Ottery FD. Clinical significance of weight loss in cancer patients: rationale for the use of anabolic agents in the treatment of cancer-related cachexia. Nutrition 2001;17(1):S1–20. [93] Kattan J, Spatz A, Culine S, et al. Hepatocellular carcinoma during hormonotherapy for prostatic cancer. Am J Clin Oncol 1994;17(5):390–2. [94] Ohri SJ, Gaer JA, Keane PF. Hepatocellular carcinoma and treatment with cyproterone acetate. Br J Urol 1991;67(2):213. [95] Watanabe S, Yamasaki S, Tanae A, et al. Three cases of hepatocellular carcinoma among cyproterone users. Ad hoc Committee on Androcur Users. Lancet 1994;344(8936): 1567–8. [96] Rudiger T, Beckmann J, Queisser W. Hepatocellular carcinoma after treatment with cyproterone acetate combined with ethinyloestradiol. Lancet 1995;345(8947):452–3.
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[97] Meijers WH, Willemse PH, Sleijfer DT, et al. Hepatocellular damage by cyproterone acetate. Eur J Cancer Clin Oncol 1986;22(9):1121–2. [98] Parys BT, Hamid S, Thompson RG. Severe hepatocellular dysfunction following cyproterone acetate therapy. Br J Urol 1991;67(3):312–3. [99] Brambilla G, Martelli A. Are some progestins genotoxic liver carcinogens? Mutat Res 2002; 512(2–3):155–63. [100] Kasper P. Cyproterone acetate: a genotoxic carcinogen? Pharmacol Toxicol 2001;88(5): 223–31. [101] Werner S, Topinka J, Wolff T, et al. Accumulation and persistence of DNA adducts of the synthetic steroid cyproterone acetate in rat liver. Carcinogenesis 1995;16:2369–72. [102] Feser W, Kerdar RS, Bauman A, et al. DNA adduct formation of selected sex steroids in human liver slices in vitro. Toxicol In Vitro 1998;12:353–64. [103] Baumann A, Kerdar RS, Cramer P, et al. Use of rat and human liver slices for the detection of steroid hormone-induced DNA adducts in vitro by means of the 32P-post-labeling technique. Pharmacol Toxicol 1996;78:214–23. [104] Martelli A, Brambilla G, Ghia M, et al. Induction of micronuclei and initiation of enzymealtered foci in the liver of female rats treated with cyproterone acetate, chlormadinone acetate or megestrol acetate. Carcinogenesis 1996;17:551–4. [105] Levesque H, Trivalle C, Manchon ND, et al. Fulminant hepatitis due to cyproterone acetate. Lancet 1989;1:215–6. [106] Murphy BJ, Collins BJ. Severe hepatitis and liver failure induced by cyproterone acetate. Aust N Z J Med 1996;26:724. [107] Friedman G, Lamoureux E, Sherker AH. Fatal fulminant hepatic failure due to cyproterone acetate. Dig Dis Sci 1999;44:1362–3. [108] Antoni M, Bourliere M, Toullec J, et al. Fatal subfulminant hepatitis caused by cyproterone acetate. Gastroenterol Clin Biol 1991;15:772–3. [109] Savidou I, Deutsch M, Soultati AS. Hepatotoxicity induced by cyproterone acetate: a report of three cases. World J Gastroenterol 2006;12(46):7551–5. [110] Kew MC, Van Coller B, Prowse CM, et al. Occurrence of primary hepatocellular cancer and peliosis hepatis after treatment with androgenic steroids. S Afr Med J 1976;50(32): 1233–7. [111] Touraine RL, Bertrand Y, Foray P, et al. Hepatic tumours during androgen therapy in Fanconi anemia. Eur J Pediatr 1993;152(8):691–3. [112] Velazquez I, Alter BP. Androgens and liver tumors: Fanconi’s anemia and non-Fanconi’s conditions. Am J Hematol 2004;77(3):257–67. [113] Kosaka A, Takahashi H, Yajima Y, et al. Hepatocellular carcinoma associated with anabolic steroid therapy: report of a case and review of the Japanese literature. J Gastroenterol 1996;31(3):450–4. [114] Ma B, Yeo W, Hui P, et al. Acute toxicity of adjuvant doxorubicin and cyclophosphamide for early breast cancer- a retrospective review of Chinese patients and comparison with an historic Western series. Radiother Oncol 2001;62:185–9. [115] Liang RH, Lok AS, Lai CL, et al. Hepatitis B infection in patients with lymphomas. Hematol Oncol 1990;8:261–70. [116] Yeo W, Steinberg JL, Tam JS, et al. Lamivudine in the treatment of hepatitis B virus reactivation during cytotoxic chemotherapy. J Med Virol 1999;59:263–9. [117] Yeo W, Chan PK, Zhong S, et al. Frequency of hepatitis B virus reactivation in cancer patients undergoing cytotoxic chemotherapy: a prospective study of 626 patients with identification of risk factors. J Med Virol 2000;62:299–307. [118] Hoofbagke JH, Dusheiko GM, Schafer DF, et al. Reactivation of chronic hepatitis B virus infection after discontinuation of low dose methotrexate therapy. Ann Intern Med 1990; 112:381–2. [119] Thung SN, Gerber MA, Klion F, et al. Massive hepatic necrosis after chemotherapy withdrawal in a hepatitis B virus carrier. Arch Intern Med 1985;145:1313–4.
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Cancer Chemotherapy II: Atypical Hepatic Injuries Edmundo A. Rodriguez-Frias, MDa, William M. Lee, MDb,* a
Department of Internal Medicine, The University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, Texas 75390, USA b Division of Digestive and Liver Diseases, The University of Texas Southwestern Medical Center at Dallas, 5959 Harry Hines Boulevard, HP-4.420, Dallas, Texas 75390-8887, USA
Although chemotherapy generally is accompanied by regular testing for liver enzyme abnormalities, atypical reactions may occur that escape ordinary detection, because hepatocyte injury is not the primary event. The presence of fatty liver, mitochondrial changes, and even biliary abnormalities can be associated with normal or nearly normal liver enzyme levels. Nonetheless, the liver is enduring ongoing damage, and an extra level of alertness is appropriate, particularly with drugs associated more frequently with these unusual hepatic reactions.
Hypersensitivity Eosinophilia, although traditionally associated with drug reactions, is quite infrequent in hepatocyte injury settings. Specific examples are rare among oncologic drugs. Dacarbazine, widely used for treatment of malignant melanoma, has been associated with a few cases of fatal liver failure. Liver biopsies have shown evidence of veno-occlusive (VOD) disease and striking eosinophilic infiltrates, suggesting an association with hypersensitivity reaction [1,2]. There have been case reports of an azathioprine-related hypersensitivity reaction that is thought to be secondary to an IgE mediated response [3]. Few other instances of true immunoallergic reactions have been reported with chemotherapeutic drugs. In the present era most reactions are associated with anti-epileptic drugs, phenytoin being the principal culprit.
* Corresponding author. E-mail address: [email protected] (W.M. Lee). 1089-3261/07/$ - see front matter Ó 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.cld.2007.06.012 liver.theclinics.com
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Cholestasis Cholestasis, obstruction to bile flow, seldom leads to liver failure but can do so in a long, indolent illness characterized by permanent bile duct injury. Relatively pure cholestatic reactions are associated with lower aminotransferase levels and more elevated alkaline phosphatase and bilirubin levels. The classic definition of cholestasis requires that the alkaline phosphatase value be more than five times the upper limit of normal and the aminotransferase levels less than two times the upper limit of normal . On biopsy, it is difficult to identify any remaining bile ducts within the portal tracts. Death results from prolonged, low-grade, systemic illness with inanition, usually in the elderly. Busulfan is rarely used for myeloproliferative disorders and is cleared quickly from the blood and excreted in urine. Liver metabolism is not relevant. It has been reported as a cause of cholestatic jaundice in two isolated cases, although one patient also had leukemic infiltration of the liver [4,5]. Chlorambucil produced cholestasis findings on autopsy in 6 of 181 patients in one series. Damage usually was seen in central areas but occasionally was midzonal or periportal [6]. Cyclophosphamide-induced hepatotoxicity usually has been reported in patients taking high cumulative doses or in those treated for a long time [7–9]. There is a single case report of acute icteric hepatitis with evidence of cholestasis and cholangitic damage determined by liver biopsy in a patient treated with low-dose cyclophosphamide for a short time [10]. Gemcitabine is a fluorine analogue of cytarabine with broad-spectrum antitumor activity. It is used in the treatment of pancreatic cancer, often with hepatic metastases. Frequently, this drug produces transient transaminase elevation, but it also has been implicated in at least four cases of fatal cholestatic hepatotoxicity [11–14]. Pre-existing liver metastases and/or a bilirubin level higher than 1.6 mg/dL at onset of treatment are considered definite risk factors for developing liver failure [15,16]. 6-Mercaptopurine is used in acute lymphocytic leukemia. It produces cholestatic injury more frequently in adults than in children. Jaundice and elevation of aspartate aminotransferase appear after 1 or 2 months of treatment and are reversible after discontinuation of the drug. Hepatic necrosis was found in rats [17–19]. There is a case report of cholestatic liver failure in association with doxorubicin [20]. Azathioprine is related to mercaptopurine. It is been used in solid-organ transplantation and in the treatment of psoriasis, rheumatoid arthritis, inflammatory bowel disease, and autoimmune hepatitis. The incidence of liver toxicity is remarkably low when compared with mercaptopurine, but the clinical presentation is similar [21]. Liver biopsies at 6 and 24 months in patients who had psoriasis and taking high doses of azathioprine showed minimal evidence of cholestasis, which was reversible after cessation of the drug, in only a few cases [22].
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Cytarabine is used in lymphoma, acute myelogenous leukemia, and myelodysplastic syndrome. High doses predict disease-free survival. One study of patients who had leukemia treated with high doses showed liver abnormalities in about 40% of cases, although in many cases there were other explanations for these changes [23]. Dose-dependent hepatotoxicity has been seen with continuous, high-dose infusions for longer than 3 days [24]. A few case reports have linked hepatotoxicity with high doses of cytarabine, as seen by liver biopsy [25,26]. With a few exceptions, the liver damage follows a cholestatic jaundice pattern, usually mild and reversible [27,28].
Hepatic steatosis The accumulation of fat within liver cells takes two forms. Microvesicular fat present within hepatocytes causes cell swelling and dysfunction. Macrovesicular fat consists of large droplets that accumulate outside hepatocytes. Recent evidence suggests that cirrhosis can develop from the presence of fatty change over a short or long time interval [29]. Oxiloplatin and irinotecan used for preoperative chemotherapy before resective surgery of hepatic metastases have been associated with severe steatohepatitis, especially in obese patients. The findings have important implications, because these observations could limit the ability to perform large liver resections in patients who have undergone this particular chemotherapy for hepatic colorectal metastases. A liver biopsy to look the histology before surgery might alter the final management of these patients [30]. Tamoxifen is a selective estrogen receptor modulator used as adjuvant treatment in estrogen receptor–positive breast cancer. The most common pattern of injury is fatty liver, reported in up to 30% of cases [31], but progression to steatohepatitis and cirrhosis is said to be rare [32–36]. One study evaluated the use of tamoxifen in patients who had known pre-existing liver steatosis and found that 43% of these patients developed hepatotoxicity, especially if they had pre-existing obesity, diabetes, or higher lipid levels. Glucose intolerance was probably the most important predictive factor [37]. Tamoxifen is associated with a twofold-increased risk of developing steatohepatitis, especially in overweight women [38]. Leptin levels, which correlate with body fat mass, are increased in tamoxifen-induced steatosis [39]. Fatty liver normally appears as early as 3 months after beginning therapy and persists for more than 4 years after discontinuation. Therefore, long-term follow-up is warranted [40]. It also has been shown in several long-term studies to be hepatocarcinogenic in rats through activation of cytochrome P-450 (CYP450) to an electrophile that binds irreversibly to the DNA. Toremifene and raloxifene do not share this side effect [41–44]. Other forms of hepatotoxicity reported in addition to steatohepatitis include peliosis hepatis [45] and acute hepatitis [46]. The benefit of using tamoxifen
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in estrogen receptor–positive breast cancer for more than 5 years might outweigh the risk of adverse effects, but this issue remains controversial [47]. In a study of toremifene in breast cancer, 7.7% patients had fatty liver as shown by CT scan, a rate that is significantly lower than historical studies in patients treated with tamoxifen. Therefore, it is suggested that patients who receive an antiestrogen agent be screened annually for fatty liver by ultrasound [48]. Exemestane is a new aromatase inhibitor used in patients who have breast cancer. A study done in patients who had liver impairment showed no important side effect in its safety profile [49]. Stilbesterol was widely used for prostate cancer in the past; however, it has largely been replaced by newer agents with superior safety profiles [50]. Steatohepatitis has been seen in animal models [51] and in one case report of a patient who received treatment for 11 years, as proved by biopsy [52]. Veno-occlusive disease The use of high doses of cyclophosphamide as preparation for bone marrow transplantation is associated with hemorrhagic cystitis, pulmonary toxicity, cardiac necrosis, and VOD, defined as occlusion of hepatic venous outflow and thought to result from direct damage to venular endothelial cells. As discussed in other articles in this issue, cyclophosphamide is metabolized by CYP450 to form 4-hydroxy-cyclophosphamide and acrolein, which are unstable and decompose into phosphoramide mustard that is especially cytotoxic for the hepatic sinusoidal endothelial cells in zone 3 where the concentration of CYP450 is highest [53,54]. In rats, direct exposure of the sinusoids to cyclophosphamide itself did not provoke toxicity; however, when the sinusoidal endothelium is exposed to cyclophosphamide metabolites, a dose-dependent toxicity is observed that can be prevented with the use of serine-methionine that can raise the level of hepatocyte glutathione [55]. There is a known association between these two metabolites and the occurrence of VOD [56–58]. High doses of cyclophosphamide, alone or in combination with autologous bone marrow transplantation, have caused hepatic VOD in up to 50% of cases. Fulminant hepatic failure complicating severe VOD is associated with multiorgan failure and has a very poor prognosis [59,60]. The incidence of VOD could be reduced if the dose of cyclophosphamide were decreased, but this reduction might compromise efficacy as well. There are several reports of partial benefit with the use of N-acetyl cysteine in the treatment of VOD. Randomized clinical trials will need to be done to support this use of N-acetyl cysteine [61]. Gemcitabine has been associated with least to one case of VOD in the literature [62]. Acute liver failure caused by vascular occlusion in patients receiving dacarbazine as single-agent chemotherapy has been noted only rarely [63]. The liver failure has been ascribed to the depletion of glutathione [64].
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The use of azathioprine in renal transplant recipients may be closely linked with the development of VOD, and this disorder may be more common than previously reported. In these patients, serum bilirubin and alkaline phosphatase levels should be monitored closely for the earliest signs of VOD [65]. A follow-up of patients after bone marrow transplantation showed threeto fourfold increase of VOD in patients who had received busulfan [66]. Like cyclophosphamide, busulfan can deplete hepatic glutathione, predisposing the patient to further liver injury. Ursodiol is a hydrophilic, water-soluble bile acid; in some studies its action as antioxidant has been shown to impart a statistically significant protection [67,68], but other studies did not demonstrate any benefit [69]. In a few cases the use of oxaliplatin has been associated with sinusoidal obstruction, with fibrotic venular occlusion seen on liver biopsies [70]. Gemtuzumab combines a monoclonal antibody with a metabolic agent, calicheamicin, that is released inside the myeloid lysosome. It has been associated with some cases of VOD, with reported incidences as low as 2% [71] and as high as 21% [72] . The risk of post-gemtuzumab VOD probably is lower after autologous stem cell transplantation than after allogeneic stem cell transplantation and with longer intervals to transplantation [73]; VOD did not occur in patients treated with gemtuzumab more than 3.5 months before stem cell transplantation [72,74]. No specific demographic or disease-related risk factors have been associated with the development of VOD after the use of gemtuzumab [75]. One of eight patients who had acute myeloid leukemia and who relapsed after hematopoietic stem cell transplantation developed severe VOD and died 14 days after treatment with gemtuzumab [76]. Arceci and colleagues [77] found a higher incidence of VOD at dosages of 6 to 9 mg/m2 in children and in adults receiving stem cell transplantation. Daptinomycin is an inhibitor of transcription normally used in children who have nephroblastoma and rhabdomyosarcoma. It has been associated with VOD in up to 5% of cases, with the median duration of 27 days, and usually is self-limiting. One study suggested that amifostine could have a protective effect in those cases [78–80]. In general, the treatment for VOD is mainly supportive. Prevention of fatal VOD is a priority and in the case of busulfan can be achieved with pharmacokinetic monitoring of drug levels with the objective of minimizing further liver damage [81]. Different authors have used supplemental hepatic glutathione experimentally, because levels of glutathione and other antioxidants seem to decline after chemotherapy in the setting of transplantation. The results are still equivocal and anecdotal; further studies are in progress [82]. The most encouraging current treatment for VOD is defibrotide, which is believed to modulate endothelial cell injury and protect the sinusoidal endothelium. It has binding sites on adenosine receptors A1 and A2 (nucleotide
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receptors that participate in endothelial cell regulation). Defibrotide decreases thrombin generation, increases prostacyclin, and inhibits deposition of fibrin and collagen with subsequent reduction of fibrosis [83–87]. The earlier the intervention with defibrotide, the more effective is the outcome. The average active dose used was 25 mg/kg/d, with response to the treatment within the first 7 days [88].
Hepatic tumors associated with chemotherapy The use of drugs that promote anabolism in the setting of chronic wasting conditions such as HIV, burn injury, chronic diseases, and cancer has advanced the supportive care for cancer patients. At the regular dose of 20 mg/d, oxandrolone generally is better tolerated than other anabolic androgenic steroids. It did not show evidence of the hepatotoxic effects such as jaundice, cholestatic hepatitis, peliosis hepatis, hyperplasias, and neoplasms seen in the group of anabolic-androgenic steroids, because oxandrolone undergoes minimal hepatic metabolism and is excreted primarily in the urine [89–91]. At higher doses, cholestasis is a theoretical possibility but has not been identified [92]. Cyproterone acetate belongs to the family of progestins and is administered in prostate and breast cancer, severe acne, and other indications. It could produce a variety of hepatotoxic reactions including hepatocellular mutagenic potency leading to hepatocarcinogenesis [93–98]. In fact, this group of drugs is classified by the International Agency for Research on Cancer as possibly carcinogenic to humans [99]. The risk seems to be low when used at standard doses for the currently authorized indications, however [100]. Different studies have shown that cyproterone forms DNA adducts and elicits DNA repair in hepatocytes [101–103]. Lesions in DNA are indicated by the increase of the frequency of micronucleated cells, mutations, and enzyme-altered preneoplastic foci in liver of female rats, but the pathophysiology of its hepatotoxicity remains unclear [104]. There are a few reports of fatality linked to the use of cyproterone because of severe hepatitis, which is more common in elderly patients and after long treatment [105–108]. In most cases hepatotoxicity resolves with iscontinuation of the drug. In general, the latency before the onset of hepatocellular carcinoma is several years [109]. Clinical surveillance in patients who have pre-existing liver disease is encouraged. It is widely known that androgens can produce liver tumors, especially in patients who have Fanconi’s anemia [110,111]. Hepatocellular carcinoma in general is associated more often with the use of oxymetholone and methyltestosterone, whereas adenoma is associated more commonly with danazol. All patients taking anabolic androgenic steroids, regardless of underlying diagnosis, are at risk of liver tumors, and patients receiving long-term treatment should undergo routine screening by liver ultrasonography [112,113].
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Reactivation of viral hepatitis Ma and colleagues [114] reported a retrospective study in Chinese women who had breast cancer treated with doxorubicin and cyclophosphamide and compared their data with an historic Western cohort. Eight patients (9.4%) had hepatitis; five had mild hepatitis, and three had moderate-to-severe hepatitis. All were positive for hepatis B surface antigen (HbsAg), suggesting that reactivation of hepatis B virus was the culprit [114]. A number of series have emphasized that reactivation is observed most commonly in the setting of lymphoma but can occur with almost any chemotherapy and in various stages of hepatitis B infection [115,116]. Patients who have HBsAg positivity in serum and who are not pretreated with lamivudine before chemotherapy have more hepatotoxicity and hepatitis B reactivation [115,116]. The degree of reactivation ranges from mild hepatitis to fatal hepatic failure [115–119]. Different drugs (eg, imatinib) have been linked to fulminant hepatitis [120], and viral reactivation should be considered in all patients undergoing chemotherapy who have history of hepatitis B. It is advisable to screen all Asian patients and anyone who has risk factors for hepatitis B for active or inactive disease before initiating any form of significant chemo- or immunotherapy. Liver fibrosis Methotrexate is used for breast cancer, head and neck cancer, osteosarcoma, acute lymphocytic leukemia, and, in lower doses for psoriasis, inflammatory bowel disease, and rheumatoid arthritis. A study in patients who had psoriasis treated with methotrexate reported that regular monitoring of liver-associated enzymes did not correlate with histologic deterioration (findings on liver biopsy ranged from mild steatosis to severe fibrosis). The evaluators suggested that routine liver biopsies are necessary to monitor for methotrexate hepatotoxicity in this subset of patients [121]. Repeat liver biopsy has long been regarded as the only reliable method of detecting liver fibrosis, and it still is recommended by the American Academy of Dermatology. Serum procollagen III aminopeptide is formed during the synthesis of type III collagen and has been used as a marker for hepatic fibrosis in patients receiving long-term therapy with methotrexate. Although the test does not detect all instances of fibrosis, the risk of missing significant liver damage in patients who have persistently normal procollagen III aminopeptide is low. Serial measurements have been advocated as a means of reducing significantly the need for liver biopsy [122–124]. Summary The dose of anticancer drugs normally used is the highest that can be given to impact a therapeutic target with minimal probability of toxicity
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[125]. There are no clear guidelines on the use of anticancer drugs in patients who have liver impairment [126]. Liver impairment may not predispose a patient to increased toxicity but is likely to affect the degree of injury in certain settings [127]. Specifically, patients at higher risk of developing VOD are those who have underlying lymphoma, hepatic metastases, stem cell transplantation, prior radiation therapy, and receive a combination of drugs, especially cyclophosphamide and busulfan [81,128–130]. The most important risk factor for the development of VOD is pre-existing liver disease, particularly elevated alanine aminotransferase levels [131]. Serum bilirubin levels and weight gain are predictors of outcome. Unfortunately the treatment for VOD is mostly supportive, because several medications evaluated for prevention have not been scrutinized in large, well-randomized, valid studies [132]. In general, many of the anticancer drugs are used intravenously, so there are few studies that relate to their oral bioavailability or hepatic excretion [133]. Therapeutic monitoring may help prevent overdose and subsequent risk for potentially life-threatening toxicity. The development of pharmacogenomic tools to individualize treatment [134] may allow better drug targeting based on the specific genetic profile of the host and possibly of the tumor [135] and may help keep dangerous side effects from happening. Chemotherapeutic agents may cause different toxicities, including hepatotoxicity, especially in patients who have baseline liver impairment. Clinical judgment is important and relies on early detection and treatment of liver injury and prompt drug withdrawal if indicated. Better guidelines, pharmacokinetic studies, and reports of cases are needed to minimize hepatotoxicity in cancer chemotherapy.
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