University of California Davis Cancer Center, Sacramento, California, USA. Key Words. Hepatic Renal Dysfunction Chemotherapy Cancer

Transcription

1 The Oncologist Clinical Pharmacology Commentary: Oncologic Drugs in Patients with Organ Dysfunction: A Summary DIANA SUPERFIN, ANDREA A. IANNUCCI, ANGELA M. DAVIES University of California Davis Cancer Center, Sacramento, California, USA Key Words. Hepatic Renal Dysfunction Chemotherapy Cancer Disclosure: A.M.D. has acted as a consultant for Bristol-Myers Squibb, Allos Therapeutics, CTI Therapeutics, Genentech, Millennium, and Lilly, and has received support from Genentech and Aventis. LEARNING OBJECTIVES After completing this course, the reader will be able to: 1. Describe the currently recommended dose adjustments for common chemotherapeutics in oncology patients with organ dysfunction. 2. Explain the rationale for using phase I dose-escalation studies to determine appropriate chemotherapy dosing in patients with organ dysfunction. 3. Discuss the limitations of the currently available studies to guide chemotherapy dose adjustment in patients with organ dysfunction. CME Access and take the CME test online and receive 1 AMA PRA Category 1 Credit at CME.TheOncologist.com ABSTRACT There are few prospective data regarding the pharmacokinetics and clinical toxicity of commonly used chemotherapeutics in cancer patients with organ dysfunction. Although increasing numbers of studies are investigating newer chemotherapeutics in patients with liver or kidney dysfunction, most guidelines for dosing, especially for established agents, remain empiric. This review describes the available data (both prospective and case study) evaluating the impact of renal and hepatic dysfunction on toxicity and dosing of commonly used chemotherapeutics and provides a practical summary for their use in this setting. The Oncologist 2007;12: INTRODUCTION Chemotherapy dosing is based on phase I dose-escalation trials in which cohorts of cancer patients with normal organ function are treated until dose-limiting toxicities (DLTs) are seen, and a maximum-tolerated dose (MTD) of the drug is determined. The MTD is then recommended for phase II testing and subsequent use in patients. The primary means of individualizing dose for most chemotherapy drugs is the use of the calculated body surface area. However, such dosage calculations do not consider pharmacokinetics (PKs) or organ function. The Calvert formula is one alternative used for calculating carboplatin doses, which incorporates an es- Correspondence: Angela M. Davies, M.D., F.R.C.P.C., Hematology/Oncology, University of California Davis Cancer Center, 4501 X Street, Suite 3016, Sacramento, California 95817, USA. Telephone: ; Fax: ; angela.davies@ucdmc.ucdavis.edu Received January 4, 2007; accepted for publication June 26, AlphaMed Press /2007/$30.00/0 doi: /theoncologist The Oncologist 2007;12:

2 Superfin, Iannucci, Davies 1071 timate of renal elimination, using measured or calculated creatinine clearance (CrCL): Dose (mg) (CrCL 25) (ml/minute) area under the concentration time curve (AUC) (mg/ml minute) [1]. However, similar formulas for individualized dosing of other chemotherapeutics are not available for widespread use. Chemotherapeutic agents are primarily metabolized or excreted in the kidneys or the liver, although some drug metabolites of hepatic origin are excreted by the kidneys (Table 1). While physicians recognize the importance of considering abnormal organ function when prescribing chemotherapy, dosing in patients with hepatic or renal dysfunction has been largely empiric. There has been an assumption that, in the presence of organ dysfunction, drugs require dose reduction; however, an inappropriate reduction in dose may lead to undertreatment of patients. On the other hand, lack of dose reduction, when clinically indicated, may lead to excessive toxicity. Many recommendations commonly employed for dose adjustments for chemotherapy drugs are derived from clinical data that are decades old and prior to the routine use of colony-stimulating factors. The data are frequently based on retrospective observations in small numbers of patients, with limited clinical information provided, and often focus only on acute toxicity risk and not long-term risks. Furthermore, when comparing recommendations for dosing across studies, there is inconsistency in the definitions used for hepatic/renal dysfunction. This review describes the published literature on chemotherapy administration and dosing in patients with organ (hepatic and renal) dysfunction and discusses its limitations. A summary of recommendations and considerations for some of the most commonly prescribed chemotherapeutics in the setting of renal or hepatic dysfunction is provided. HEPATIC DYSFUNCTION Hepatic dysfunction in patients with cancer can occur as a result of pre-existing disease processes (such as Gilbert s disease or viral-/drug-induced cirrhosis) or from metastatic invasion. The PKs of hepatically cleared drugs can be affected by: (a) altered clearance resulting from decreased hepatocyte uptake or impaired liver blood flow, (b) altered biliary excretion, (c) altered metabolic capacity, (d) decreased albumin production resulting in increased free drug, or (e) altered oral drug absorption from portal hypertension. Given these factors, most clinical trials exclude patients with significant liver dysfunction [2]. One of the challenges in interpreting recommendations is the definition of liver dysfunction. Definitions of liver dysfunction vary in trials, and in the absence of reliable dose-modification schemes, inconsistent dose adjustments are often made outside of a clinical trial. Dose adjustments are frequently based on the total serum bilirubin level, or transaminase levels (aspartate aminotransferase [AST] or alanine aminotransferase [ALT]). However, total serum bilirubin may not universally reflect histological damage to the liver, while elevations in hepatic transaminases are indicators of damage to the liver, but are not necessarily reflective of hepatic function. Neither of these parameters alone or in combination is ideal in assessing hepatic function, but more dynamic liver function tests, such as the antipyrine test, galactose elimination capacity, bromosulphthalein clearance, and the mono-ethylglycine-xylidide test, are too cumbersome for use in daily clinical practice [2]. Alternatively, the role of the Child-Pugh classification (Table 2) of hepatic dysfunction, used by many liver transplant surgeons to estimate hepatic reserve and prognosis in chronic liver disease, in the dosing of drugs is unclear. Additionally, it could be argued that, for patients with chemosensitive tumors (e.g., breast cancer, germ cell tumors, lymphoma) who have hepatic impairment resulting from metastatic disease, treatment at the recommended doses may offer the best approach to correcting hepatic function [3, 4]. However, most studies do not distinguish between liver dysfunction caused by cancer and liver dysfunction from other causes. In addition to the underlying cause and severity of liver dysfunction, clinicians have to consider supportive care measures, such as growth factors available to support the patient through the period of myelosuppression, the potential risks for nonhematologic toxicities (e.g., mucositis, cardiac toxicity), underlying comorbid conditions, performance status, additional risk factors for infection or complications from chemotherapy, the malignancy type, whether or not dose intensity is important, and the ultimate goals of therapy (curative intent versus palliation). Recognizing the importance of these issues, several review articles have attempted to provide guidelines for dosing of chemotherapeutics in oncology patients with liver dysfunction [2, 5, 6]. Anthracyclines Doxorubicin Anthracyclines are extracted from the plasma and metabolized to side chain alcohol and aglycone derivates by the liver; then, the drugs and their metabolites are excreted in the bile with an insignificant amount appearing in the urine. Thirty years ago, Benjamin [7] reported greater toxicity (pancytopenia, painful mucositis, and three drug-related deaths) in a limited patient sample (eight patients) with liver dysfunction (bilirubin 3 mg/dl) treated with full-dose

3 1072 Chemotherapy Dosing in Organ Dysfunction Table 1. Metabolism and excretion of commonly used chemotherapeutic agents Agent Metabolism Excretion Dose reduction required? All-trans-retinoic acid Hepatic Renal Consider Arsenic trioxide Hepatic Hepatic No Asparaginase RES Hepatic, RES No Azacitidine Hepatic Renal Yes (renal) Bexarotene Hepatic Hepatic No Bleomycin Hepatic, gut Renal Yes (renal) Bortezomib Hepatic Renal, hepatic No Busulfan Hepatic Renal No Capecitabine Hepatic Renal Yes (renal) Carboplatin Renal Yes (renal) Carmustine Hepatic Renal No Cetuximab Tissue Tissue No recommendations Chlorambucil Hepatic Hepatic No Cisplatin Renal Yes (renal) Cladribine Not described Renal No recommendations Cyclophosphamide Hepatic Renal No, for standard dose; yes (renal), for high dose Cytarabine Hepatic Renal Yes (renal) Dacarbazine Hepatic Renal Consider (renal) Daunorubicin Hepatic Hepatic Yes (hepatic) Dasatinib Hepatic Feces No recommendations Decitabine Tissue Tissue Docetaxel Hepatic Hepatic Yes (hepatic) Doxorubicin Hepatic Hepatic Yes (hepatic) Epirubicin Hepatic Hepatic Yes (hepatic) Erlotinib Hepatic Hepatic Consider Estramustine Hepatic Hepatic, feces No Etoposide Hepatic Renal, hepatic Consider (hepatic, renal, low albumin) Fludarabine Tissue Renal Yes (renal) Fluorouracil Hepatic Renal, hepatic No Gefitinib Hepatic Hepatic, feces No Gemcitabine Hepatic Renal Yes (hepatic) Hydroxyurea Hepatic Renal Consider (renal) Idarubicin Hepatic Renal, hepatic Consider (severe hepatic dysfunction) Ifosfamide Hepatic Renal Yes (renal) Imatinib mesylate Hepatic Renal, feces Yes (for hepatotoxicity on treatment) Interferon- Renal Renal No Interleukin-2 Renal Renal No Irinotecan Hepatic Renal, hepatic Yes (hepatic) Ixabepilone Hepatic Yes (hepatic) Lenalidomide Renal No recommendations Lomustine Hepatic Renal No Mechlorethamine Blood Blood No Melphalan Blood Renal Yes (renal) Mercaptopurine Hepatic Renal No clear recommendations Methotrexate Hepatic Renal Yes (renal, hepatic) (continued)

4 Superfin, Iannucci, Davies 1073 Table 1. (Continued) Agent Metabolism Excretion Dose reduction required? Mitomycin Hepatic Hepatic No Mitoxantrone Hepatic Hepatic, feces Yes Oxaliplatin Plasma Renal Consider (severe renal dysfunction) Paclitaxel Hepatic Hepatic Yes (hepatic) Pemetrexed Renal No recommendations Pentostatin Renal Yes (renal) Procarbazine Hepatic, renal Renal, feces Consider (renal or severe hepatic dysfunction) Temozolomide Plasma Renal, other No Thalidomide Other No Thiotepa Hepatic No Topotecan Hepatic Renal Yes (renal) Vinblastine Hepatic Hepatic Yes (hepatic) Vincristine Hepatic Hepatic Yes (hepatic) Vinorelbine Hepatic Hepatic Yes (hepatic) Abbreviation: RES, reticuloendothelial system. Table 2. Modified Child-Pugh score Manifestation One point Two points Three points Encephalopathy a None Grade I II Grade III IV Ascites Absent Nontense Tense Bilirubin (mg/dl) Noncholestatic Cholestatic Abumin (g/dl) INR a Encephalopathy: I, mild confusion or slowing, no asterixis; II, drowsy, asterixis present; III, marked confusion, somnolence, asterixis present; IV, unresponsive or responsive only to painful stimuli, no asterixis. Class A, 5 6 points; class B, 7 9 points; class C, 10 points. Abbreviation: INR, international normalized ratio. doxorubicin. In a follow-up study of nine additional patients with liver dysfunction, the authors concluded that the doxorubicin dose should be reduced in the setting of hepatic dysfunction to prevent toxicity from drug accumulation, and recommended a 50% dose reduction for bilirubin levels of 2 3 mg/dl or for AST/ALT levels 3 the upper limit of normal (ULN), a 75% dose reduction for bilirubin levels of 3 5 mg/dl, and omitting doxorubicin for bilirubin levels 5 mg/dl [8]. Since then, these recommendations have been widely incorporated into clinical practice despite the fact that the recommendations were based on a very small number of patients with hepatic dysfunction of unspecified origin. Subsequent studies have shown contradictory results with doxorubicin administration in patients with hepatic dysfunction. Donelli et al. [2] reported that administration of full-dose doxorubicin in mild hepatic dysfunction (bilirubin 2 ULN) did not result in clinically significant greater toxicity. Those authors recommended dose adjustment (not specified) for serum bilirubin levels 3 mg/dl. Successful doxorubicin administration with attenuated doses in patients with more severe hepatic impairment (bilirubin 5 mg/dl) has been described, but only in case reports [9]. Those studies did not incorporate transaminases into the dose-modification schema. The primary toxicity associated with greater doxorubicin exposure in patients with hyperbilirubinemia is myelosuppression. As the majority of these studies were published in the 1980s and early 1990s, G-CSF support was not commonly available to manage myelosuppression. Although there is the obvious concern over the potential impact of higher exposure to doxorubicin on cardiac toxicity, this effect has not been clearly described in these small studies, which primarily evaluated the acute toxicities of doxorubicin in this setting. However, concern may be warranted for potential lower antitumor effects with doxorubicin dose reduction, as was suggested in one study in patients with acute myelogenous leukemia (AML) and liver dysfunction (cause not specified), where shorter durations of response and survival were noted in the setting of dose reduction [10]. Idarubicin Using multiple hepatic parameters, prospective studies examining idarubicin in patients with mild-to-moderate liver

5 1074 Chemotherapy Dosing in Organ Dysfunction dysfunction (serum bilirubin ULN, gamma-glutamyl transferase 2 8 ULN, and alkaline phosphatase [ALP] ULN) demonstrated no PK alteration or greater toxicity [11]. Using a slightly different definition of mild-to-moderate liver dysfunction (AST ULN, ALT ULN, and ALP ULN), Camaggi et al. [12] found no significant PK alterations. While the authors concluded that no dose reductions were required in the presence of mild-to-moderate hepatic impairment, the data were insufficient to make recommendations for patients with severe hepatic impairment. Epirubicin Based on an evaluation of epirubicin PKs in 53 advanced breast cancer patients, AST is a more sensitive and reliable marker of epirubicin clearance than bilirubin [13]. Using a transaminase-based approach, Dobbs et al. [14] identified a target AUC for epirubicin in breast cancer patients with normal liver function, and then validated an AST-based dosing scheme in 16 patients with abnormal liver biochemistry. Ralph et al. [15] developed more precise AST-based dosage guidelines studying 109 patients with advanced breast cancer, 72 of whom had liver metastases (Table 3). Topoisomerase Inhibitors Etoposide Etoposide is partially metabolized into inactive forms in the liver and cleared by both the liver and the kidneys. Four studies have demonstrated that mild-to-moderate liver dysfunction (bilirubin 1 2 mg/dl) does not affect etoposide PKs, but severe impairment (not clearly defined) can contribute to greater toxicity (myelosuppression, mucositis) because of reduced hepatobiliary metabolism [16 19]. In addition, albumin levels have been identified as important, with a higher fraction of unbound etoposide being directly related to high serum bilirubin and low albumin, which can lead to greater hematological toxicity [20]. However, the pharmacologic effects may not be altered at all in those patients with hepatic dysfunction and hypoalbuminemia resulting from greater renal clearance [21]. Because of the potential for compensatory elimination of etoposide in patients with hepatic and/or renal dysfunction, specific guidelines for etoposide dosing in these patients are difficult to define. Irinotecan Irinotecan is primarily metabolized into its active metabolite, SN-38, and then eliminated hepatically; the drug and its metabolites are also partially excreted renally. In a phase I study of patients with liver dysfunction, hyperbilirubinemia resulted in lower biliary excretion of irinotecan and higher drug exposure, leading to DLTs of febrile neutropenia and diarrhea. The investigators noted that serum bilirubin levels of ULN required a dose reduction from 350 mg/m 2 to 200 mg/m 2 every 3 weeks to prevent severe toxicity [22]. Venook et al. [23] evaluated four treatment cohorts: (a) AST 3 ULN and direct bilirubin 1 mg/dl, (b) direct bilirubin 1 7 mg/dl, (c) creatinine mg/dl with normal liver function, and (d) prior pelvic radiotherapy with normal liver and renal function. They recommended a dose reduction for patients with liver impairment (direct bilirubin 1 mg/dl) to reduce toxicity. In contrast to the previous study, these investigators did not observe dose-limiting diarrhea in patients with elevated direct bilirubin levels as high, suggesting that this was consistent with the hypothesis that SN-38 biliary excretion is responsible for causing diarrhea in patients receiving irinotecan, and that SN-38 biliary excretion would be impaired in patients with hyperbilirubinemia and cholestasis [23]. Topotecan Topotecan is metabolized by ph-dependent hydrolysis and, to a lesser extent, by the liver. No dose adjustment is recommended in patients with impaired liver function based on a case cohort study (bilirubin mg/dl) [24]. Oxaliplatin Although the liver has no direct role in oxaliplatin metabolism, it is a highly protein-bound compound (approximately 85%); thus, low albumin levels can affect drug PKs. Oxaliplatin PKs in patients with impaired liver function were examined in a prospective phase I study in patients with varying degrees of liver dysfunction (defined by serum bilirubin, AST, and ALP), and there was no impact on clearance or toxicity (neurotoxicity) [25]. Gemcitabine Gemcitabine is extensively deaminated by cytidine deaminase to its inactive metabolite, and then excreted through the kidneys. A phase I study of gemcitabine in patients with hepatic and renal dysfunction showed that elevated AST had no impact on drug clearance or toxicity. However, administration of gemcitabine in the presence of elevated bilirubin ( mg/dl) had a significant impact on hepatotoxicity as noted by further, marked elevations in serum bilirubin and transaminase levels. Given that these abnormal values were transient, their clinical relevance is unclear. The authors concluded that patients with elevated serum bilirubin should receive a lower weekly gemcitabine dose of 800 mg/m 2, and subsequently be given escalating doses if the therapy is tolerated [26].

6 Superfin, Iannucci, Davies 1075 Table 3. Recommended dose adjustment for liver and kidney dysfunction Drug Dysfunction Dose Doxorubicin Bilirubin 2 3 mg/dl Consider reduction by up to 50% Bilirubin mg/dl Consider reduction by up to 75% Bilirubin 5 mg/dl Omit Idarubicin No adjustment is required Epirubicin AST 150 IU/l No adjustment is required AST IU/l Reduce by 25% AST IU/l Reduce by 50% AST 500 IU/l Reduce by 75% Etoposide Bilirubin mg/dl Consider reduction by up to 50% Bilirubin 3 mg/dl Consider reduction or omitting Low albumin Consider reduction Creatinine 1.4 mg/dl Consider reduction by up to 30% Irinotecan Bilirubin ULN 200 mg/m² every 3 weeks Bilirubin median, 2.1 mg/dl; range, mg/dl 115 mg/m² every 3 weeks No adjustment is required Topotecan No adjustment is required CrCL 40 ml/min No adjustment is required CrCL ml/min Reduce by 50% Oxaliplatin No adjustment is required CrCL 20 ml/min No adjustment is required Gemcitabine Mild to moderate Reduce by 20%, increase as tolerated Vincristine, vinblastine Bilirubin mg/dl Reduce by 50% Bilirubin 3 mg/dl Omit Vinorelbine Bilirubin mg/dl Reduce by 50% Bilirubin 3 mg/dl Reduce by 75% 75% liver metastases Reduce by 50% (continued)

7 1076 Chemotherapy Dosing in Organ Dysfunction Table 3. (Continued) Drug Dysfunction Dose Paclitaxel Bilirubin mg/dl 100 mg/m² over 3 hours Bilirubin 3 mg/dl 50 mg/m² over 3 hours Increased AST Reduction is required Docetaxel Bilirubin 1 ULN Omit AST/ALT 1.5 ULN and ALP 2.5 ULN Omit 5-FU No adjustment is required No adjustment is required Capecitabine No adjustment is required CrCL ml/min Reduce by 75% CrCL 30 ml/min Omit Cytarabine Cr mg/dl or Cr mg/dl Reduce dose to 1g/m²/dose Cr 2 mg/dl or Cr 1.2 mg/dl Reduce dose to 0.1g/m²/day Methotrexate CrCL ml/min Reduce by 35% CrCL ml/min Reduce by 50% CrCL 30 ml/min Omit Cyclophosphamide No adjustment is required Mild to moderate No adjustment is required Severe Ifosfamide CrCL ml/min Reduce by 20% CrCL ml/min Reduce by 25% CrCL 30 ml/min Reduce by 30% Bleomycin CrCL ml/min Reduce by 30% CrCL ml/min Reduce by 40% CrCL ml/min Reduce by 48% CrCL ml/min Reduce by 54% Pemetrexed CrCL 40 ml/min (continued)

8 Superfin, Iannucci, Davies 1077 Table 3. (Continued) Drug Dysfunction Dose Imatinib (on treatment) Bilirubin 3 ULN or AST/ALT 5 ULN Hold treatment until bilirubin 1.5 ULN and AST/ALT 2.5 ULN and resume at a reduced dose (e.g., 400 mg to 300 mg, 600 mg to 400 mg, 800 mg to 600 mg) No adjustment is required Ixabepilone Liver function Bilirubin 1.5 ULN Study ongoing Bilirubin ULN Reduce by 25% Bilirubin 3 ULN Study ongoing Bortezomib CrCL 20 ml/min Study ongoing Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; CrCL, creatinine clearance; ULN, upper limit of normal. Vinca Alkaloids Vincristine and Vinblastine Vinca alkaloids are metabolized by hepatic microsomes with drugs and metabolites, then excreted into bile. A small amount is reabsorbed by the gut and undergoes enterohepatic recirculation. Although small amounts of the drugs are excreted in the urine, this is of no clinical significance. Given that the biliary system is the main elimination route for vinca alkaloids, it is not surprising that hepatic dysfunction is associated with greater toxicity. Desai et al. [27] examined the PKs of vincristine in 27 patients with elevated ALP (but without recording the actual values) and Chong et al. [28] evaluated vinblastine; they found that dose reductions in patients with hepatic dysfunction (not clearly defined) reduced the toxicity of these drugs (neuropathy, stomatitis). Current recommendations for these agents are to reduce doses by 50% for patients with a serum bilirubin level of mg/dl, and hold the drugs if bilirubin is 3 mg/dl. Vinorelbine Based on the PKs from breast cancer patients with liver dysfunction resulting from liver metastases, and taking into account that vinorelbine is much less neurotoxic than other vinca alkaloids, Robieux et al. [29] recommended dose adjustments of vinorelbine in patients with severe liver dysfunction (defined as obvious signs of liver failure: hyperbilirubinemia, elevated transaminases, and prothrombin time in the context of numerous confluent liver metastases), but not in patients with moderate secondary liver involvement (at least 25% normal liver parenchyma) to prevent myelosuppression. Although a weak correlation exists between serum bilirubin level and vinorelbine clearance, current adjustments for this agent are based on serum bilirubin [29]. Taxanes The taxanes, paclitaxel and docetaxel, are primarily metabolized to their inactive derivatives by the liver and excreted in the biliary system [30]. Paclitaxel Venook et al. [31] prospectively studied the PKs of both the 24-hour and 3-hour infusions of paclitaxel in patients with hepatic dysfunction, and found that dose reductions were necessary in patients with elevated AST or bilirubin (cohorts: (a) AST 2 ULN and bilirubin 1.5 mg/dl, (b) bilirubin mg/dl with any level of AST, and (c) bilirubin 3 mg/dl with any level of AST) to prevent myelosuppression and neutropenic sepsis related deaths. Investigators found that, for a 24-hour infusion of paclitaxel, doses mg/m 2 were not tolerated by patients with liver dysfunction. For the 3-hour infusion, doses of 100 mg/m 2 could be given to patients with moderate liver dysfunction, but for patients with severe liver impairment (bilirubin 3 mg/dl), doses had to be reduced to 50 mg/m 2 [31]. Docetaxel Dose reduction is also recommended for docetaxel in patients with liver dysfunction because of the higher risk for

9 1078 Chemotherapy Dosing in Organ Dysfunction neutropenia, mucositis, and treatment-related death [32, 33]. Some authors have recommended omitting the drug for patients with serum bilirubin 1 ULN or AST/ALT 1.5 ULN concomitant with ALP 2.5 ULN [34]. Dose adjustment has not been studied in docetaxel given on a weekly basis as compared with the traditional every-3- weeks regimen. 5-Fluorouracil 5-Fluorouracil (5-FU) is primarily metabolized by the enzyme dihydropyrimidine dehydrogenase (DPD), which is predominantly in the liver, to inactive metabolites. Severe toxicity in the absence of liver dysfunction can be observed in patients with inherent DPD deficiency. Fleming et al. [35] examined the PKs with a 24-hour 5-FU infusion with leucovorin in three cohorts of patients with varying degrees of organ dysfunction mild-to-moderate renal dysfunction (serum creatinine mg/dl), mild-to-moderate hepatic dysfunction (serum bilirubin mg/dl), and moderateto-severe liver dysfunction (serum bilirubin 5 mg/dl) and demonstrated that patients in all cohorts could be safely treated with a weekly continuous i.v. infusion over 24 hours without adjustment for either renal or hepatic organ dysfunction [35]. Capecitabine Capecitabine, the oral prodrug of 5-FU, is activated in the liver, and subsequently in human tumor tissue to 5-FU. 5-FU is further metabolized to dihydrofluorouracil and then -fluoro- -alanine. Twelves et al. [36] found that mild-tomoderate hepatic dysfunction (mean bilirubin, 6.5 mg/dl; range, mg/dl) had no clinical significance on the PKs of capecitabine. exist for severe hepatic dysfunction. Cytarabine Although cytarabine is metabolized by the liver into active (as well as inactive) neurotoxic metabolites, these metabolites are excreted by the kidneys. In spite of a correlation between elevated serum bilirubin and neurotoxicity, no algorithm for cytarabine dosing in patients with hepatic dysfunction has been developed [37]. Oxazaphosphorines Cyclophosphamide Cyclophosphamide is extensively metabolized in the liver, first to its active moiety 4-hydroxy-cyclophosphamide, then to the inactive compounds 4-keto- and 4-carboxycyclophosphamide. Although there has been some concern that biotransformation to its active form may be impaired in patients with liver dysfunction, PK studies have not demonstrated any difference in the overall exposure to active metabolites of cyclophosphamide, even in patients with severe liver dysfunction. Thus, no recommendations exist to alter cyclophosphamide doses in patients with hepatic dysfunction [2]. Ifosfamide Ifosfamide undergoes the same hepatic activation and metabolism as cyclophosphamide, but no recommendations exist for dose reduction of this agent in the presence of hepatic dysfunction [2]. Imatinib Imatinib is predominantly metabolized in the liver and excreted through the biliary system. Bauer et al. [38], in a case report of two patients with abnormal liver function resulting from a gastrointestinal stromal tumor, showed that imatinib could be administered without unexpected and/or serious toxicities. Eckel et al. [39] came to a similar conclusion while studying imatinib PKs in patients with impaired liver function and advanced hepatocellular carcinoma. However, because imatinib has been associated with causing hepatotoxicity, the drug s manufacturer recommends interrupting and/or reducing doses for patients who develop this toxicity while receiving imatinib (Table 3) [40]. Epothilone B Analogues Ixabepilone is an epothilone B analogue that stabilizes microtubules. While this drug is yet to be approved by the U.S. Food and Drug Administration, there are promising data in a number of solid tumors, including breast and prostate cancers. The standard dose is 40 mg/m 2 i.v. over 3 hours every 21 days. Ixabepilone is metabolized primarily in the liver and is a cytochrome P450 3A4 enzyme substrate. A phase I study in patients with advanced solid tumors with varying degrees of liver dysfunction accrued patients in five different cohorts based on bilirubin and transaminase levels. Moderate-to-severe hepatic dysfunction was associated with a lower MTD of ixabepilone as well as altered clearance, with a higher AUC. Thus, they determined that a 50% dose reduction was required for patients with bilirubin levels ULN because of greater toxicity. In the setting of mild hepatic impairment, further recommendations are pending [41]. RENAL DYSFUNCTION While hepatic dysfunction is much more commonly encountered in the oncology patient population, renal dysfunction resulting from pre-existing comorbidities or complications of the cancer itself bears consideration for

10 Superfin, Iannucci, Davies 1079 drugs that are primarily metabolized or excreted by the kidneys. The PKs of renally cleared drugs can be affected by: (a) altered kidney metabolic capacity, (b) altered renal excretion because of either altered blood flow to the kidneys or cancerous destruction of the organ, or (c) production of toxic compounds damaging the kidneys. While the Calvert formula can be helpful in dosing carboplatin in the setting of renal dysfunction, common renal function tests (e.g., serum creatinine, CrCL) can be inaccurate in predicting actual renal function, and similar formulas are not available for other renally cleared drugs. Compared with hepatic dysfunction, there is a paucity of literature with guidelines for dosing in patients with renal impairment; again dose reductions are based on data that are limited and primarily empiric. Anthracyclines The PKs of anthracyclines and their metabolites in the setting of renal dysfunction may correlate to some degree with CrCL, but there are no PK data to support dose adjustment in the presence of impaired renal function [42]. Topoisomerase Inhibitors Etoposide Arbuck et al. [17] studied etoposide PKs in patients with impaired and normal renal and hepatic function and found that etoposide clearance was primarily predicted by CrCL ( or 70 ml/minute per 1.73m 2 ) and secondarily by albumin levels. Further studies have supported the importance of renal function in etoposide PKs and toxicity recommending a 30% dose reduction in patients with a creatinine levels 1.4 mg/dl [43, 44]. In the rare setting of patients on hemodialysis receiving chemotherapy, hemodialysis did not decrease the etoposide serum concentration, presumably secondary to high plasma protein binding, but dose reduction for this population was not studied [21]. Despite these studies, specific guidelines for etoposide dosing in patients with hepatic/ renal dysfunction or hypoalbuminemia are not clearly defined. As mentioned previously, because of the potential for compensatory elimination of etoposide in patients with hepatic and/or renal dysfunction, specific guidelines for etoposide dosing are difficult to define. Thus, when deciding whether to adjust etoposide doses for renal dysfunction, the risks for potential toxicities (e.g., myelosuppression) against the benefits and goals of treatment must be considered. Irinotecan Venook et al. [23] evaluated four treatment cohorts (a) AST 3 ULN and direct bilirubin 1 mg/dl, (b) direct bilirubin 1 7 mg/dl, (c) creatinine mg/dl with normal liver function, and (d) prior pelvic radiotherapy with normal liver and renal function and concluded that no dose adjustment is required for patients with renal impairment taking irinotecan. Topotecan About 50% of topotecan is renally excreted, and Gallo et al. [45] attempted to create a linear two-compartment population PK model for patients with compromised renal function using a multifactorial approach, including total clearance, volume of the central compartment, distributional clearance, and volume of the peripheral compartment. However, this model has not been prospectively validated. Based on topotecan PKs in patients with moderate renal dysfunction (CrCL ml/minute), the manufacturer s prescribing information recommends a 50% dose reduction to prevent severe myelosuppression for this patient population [46]. Oxaliplatin Oxaliplatin elimination is primarily renal, with the rest by biotransformation to inactive platinum-containing species and tissue distribution. A phase I study examining patients with varying degrees of renal impairment concluded that the standard oxaliplatin dose of 130 mg/m 2 was well tolerated in patients with CrCL 20 ml/minute, and no dose reductions were required in this setting [47, 48]. Patients with CrCL 20 ml/minute were not evaluated. Gemcitabine Venook et al. [26] noted greater toxicity (skin, diarrhea, transaminitis) with gemcitabine in patients with renal dysfunction (creatinine mg/dl), but were unable to generate a dose-adjustment schema, partially because of the unpredictability of the gemcitabine toxicity profile and the small number of patients. Thus, no recommendations for dose adjustment in patients with renal dysfunction currently exist. 5-FU Although Fleming et al. [35] demonstrated that patients with mild-to-moderate renal dysfunction (serum creatinine mg/dl) could safely receive a 24-hour 5-FU infusion, Cassidy et al. [49], using creatinine clearance, noted that more than half of the patients with moderate renal dysfunction (CrCL ml/minute) required 5-FU dose reductions because of grade 3 or 4 treatment-related toxicities,

11 1080 Chemotherapy Dosing in Organ Dysfunction such as stomatitis and diarrhea. Unfortunately, the authors did not generate a dose-adjustment schema. Capecitabine Poole et al. [50] noted that, although the PKs of capecitabine and 5-FU were not affected by renal dysfunction, it led to greater systemic exposure to their metabolites, 5-deoxy-5- fluorouridine and -fluoro- -alanine. Poole et al. [50] evaluated capecitabine in groups of patients with varying degrees of renal dysfunction and recommended a dose reduction by 75% for patients with moderate renal impairment (CrCL mg/dl) to decrease toxicity (diarrhea, hand foot syndrome, neutropenia). In their study, Cassidy et al. [49] suggested a similar dose adjustment. These recommendations were based on the higher AUC of the key metabolites compared with those in patients with normal renal function. Cytarabine High-dose cytarabine (HDAC) for treatment of AML in patients with renal dysfunction has been associated with a higher risk for neurotoxicity, such as acute cerebellar syndrome, encephalopathy, seizure, and even coma. Neurotoxicity with HDAC is thought to be related to accumulation of the neurotoxic metabolite ARA-CTP in the cerebrospinal fluid in patients with renal insufficiency [22]. In their retrospective analysis, Smith et al. [37] devised a dose-modification algorithm for patients with renal impairment based on serum creatinine: (a) for patients with creatinine levels of mg/dl or an increase in creatinine during treatment of mg/dl, the cytarabine dose was reduced from 2 3 g/m 2 per day to 1 g/m 2 per day; and (b) for patients with creatinine levels 2 mg/dl or a change in creatinine 1.2 mg/dl, the dose was decreased to 0.1 g/m 2 per day. Methotrexate Given that methotrexate is primarily eliminated renally, renal function is of utmost importance for methotrexate dosing. Numerous medications, including salicylates, penicillin, probenecid, and some proton pump inhibitors, may interfere with renal secretion/excretion of methotrexate [51 53]. In addition, it is not efficiently removed by standard hemodialysis. Methotrexate doses must be reduced in patients with renal dysfunction, and its use should be avoided in patients with severe renal impairment (CrCL 30 ml/minute). Kintzel and Dorr [42], in their summary, provided dosing guidelines for methotrexate in the setting of moderate renal dysfunction: a 35% reduction for a CrCL of ml/minute and a 50% reduction for a CrCL of ml/minute. Oxazaphosphorines Cyclophosphamide Cyclophosphamide is partially metabolized in the kidneys and lungs. However, most of its metabolites are excreted renally. Bramwell et al. [54] studied its disposition in myeloma patients and found that no dose reduction was required in patients with moderate renal dysfunction (not clearly defined), but that dose modification may be required in patients with severe renal failure (defined as CrCL 20 ml/minute), or if large doses of the drug are administered [54, 55]. However, no clear guidelines exist to define dose adjustment based on the degree of renal insufficiency. Cyclophosphamide is readily dialyzable, with as much as 50% of a dose removed by hemodialysis; therefore, if administered to patients on dialysis, doses should be administered following hemodialysis [56]. Ifosfamide Significant proportions of ifosfamide and its metabolites are excreted in the urine [42], and because of the greater risk for central nervous system toxicity, ifosfamide doses should be decreased in the presence of renal dysfunction. A dosing regimen based on CrCL has been proposed by Kintzel and Dorr [42]: a 20% reduction for a CrCL of ml/min, a 25% reduction for a CrCL of ml/minute, and a 30% reduction for a CrCL of 30 ml/minute. Bleomycin The major DLT of bleomycin is interstitial pneumonitis, with a 1% 2% incidence of fatal lung damage. Sixty percent of bleomycin is cleared by the kidneys, and renal dysfunction may lead to a higher risk for bleomycin pulmonary toxicity. After investigating bleomycin PKs in 26 patients with renal impairment, Dalgleish et al. [57] suggested a dose modification scheme (a) for a CrCL of ml/ minute, a dose reduction to 70%; (b) for a CrCL of ml/minute, a reduction to 60%; (c) for a CrCL of ml/ minute, a reduction to 52%; and (d) for a CrCL of ml/minute, a reduction to 46%. Pemetrexed Pemetrexed undergoes minimal metabolism prior to being primarily renally excreted. Recently, Mita et al. [58] showed no greater toxicity with standard doses of pemetrexed at 500 mg/m 2, when administered (with vitamin supplementation) to patients with CrCL 40 ml/minute, but they failed to provide dosing recommendations for patients with lower CrCLs. Although no clear guidelines exist, caution is warranted in administering pemetrexed to

12 Superfin, Iannucci, Davies 1081 patients with renal insufficiency (CrCL 40 ml/minute) until further PK and toxicity data are available. Imatinib While imatinib is primarily hepatically cleared, data with this agent in the setting of renal dysfunction are limited. Pappas et al. [59] presented a case study in one patient with end-stage renal disease taking imatinib for 1 year and suggested that it could be safely administered in this patient population. Bortezomib Bortezomib, a novel proteasome inhibitor approved for use in refractory multiple myeloma and mantle cell lymphoma, is inactivated by oxidative deboronation in the body and eliminated renally. A phase I dose escalation study in adult cancer patients with renal impairment evaluated five different cohorts of patients with varying degrees of renal impairment from normal function (CrCL 60 ml/minute) to dialysis dependence. The approved dose of 1.3 mg/m 2 on days 1, 4, 8, and 11, every 21 days, was found to be safe and well tolerated by patients with CrCL 20 ml/minute [60]. Further evaluation of patients with CrCL 20 ml/minute is ongoing. Jagannath et al. [61] reported their experience with bortezomib in patients with recurrent/refractory multiple myeloma and varying degrees of renal function (CrCL 80 ml/minute, ml/minute, and 50 ml/minute). All groups of patients had similar rates of discontinuation and similar adverse event profiles. CONCLUSIONS Organ dysfunction in cancer patients is a common occurrence, and it is assumed that dose reductions are required in this setting. Most dose adjustments are empiric, and while adjustments are needed with some chemotherapeutics to prevent excessive toxicity, the risk of undertreating the disease remains a concern. Given that conventional dosing of these compounds is established in phase I studies in patients without organ dysfunction, little is known about how to optimally dose in patients with hepatic or renal impairment, especially if this impairment is tumor related. In the past, several small cohort and case studies have attempted to look at these specific cohorts of patients and made recommendations for dosing. Given the recognition that hepatic and renal impairment can have an unpredictable impact on the metabolism and clearance of chemotherapeutic drugs, the National Cancer Institute-sponsored Organ Dysfunction Working Group is leading an effort to formally assess promising or recently approved agents in patients with organ dysfunction. These phase I dose-escalating studies evaluate different cohorts of patients defined by their degree of organ dysfunction and collect PK and clinical toxicity data with the goal to develop formal guidelines for dosing in these specific populations [62]. Despite this effort for new drugs, many commonly used agents will likely never be evaluated in this manner. In applying empiric recommendations for dose adjustments, decisions should be made on an individual patient basis, rather than globally applied on the basis of laboratory parameters alone. Factors to consider in addition to organ function include cancer type, inherent chemosensitivity, and the goals of treatment. Supportive care measures (e.g., colony-stimulating factors) should be considered to manage hematologic toxicity. Individual risk factors for complications of treatment, such as performance status, history of prior treatment, and comorbid medical conditions, are also important, as with any cancer patient treatment decision. In weighing the benefits and risks of administering chemotherapy to these patients, one may choose to use full doses for a patient with potentially curable disease, in contrast to a patient being treated with palliative intent. Based on the above information, we have summarized dose adjustment recommendations for renal and hepatic dysfunction in Table 3. REFERENCES 1 Calvert AH, Newell DR, Gumbrell LA et al. Carboplatin dosage: Prospective evaluation of a simple formula based on renal function. J Clin Oncol 1989;7: Donelli MG, Zucchetti M, Munzone E et al. Pharmacokinetics of anticancer agents in patients with impaired liver function. Eur J Cancer 1998;34: Mano MS, Cassidy J, Canney P. Liver metastases from breast cancer: Management of patients with significant liver dysfunction. Cancer Treat Rev 2005;31: Ghobrial IM, Wolf RC, Pereira DL et al. Therapeutic options in patients with lymphoma and severe liver dysfunction. Mayo Clin Proc 2004;79: Perry MC. Chemotherapeutic agents and hepatotoxicity. Semin Oncol 1992;19: Eklund JW, Trifilio S, Mulcahy MF. Chemotherapy dosing in the setting of liver dysfunction. Oncology (Williston Park) 2005;19: ; discussion , Benjamin RS. Pharmacokinetics of Adriamycin (NSC ) in patients with sarcomas. Cancer Chemother Rep 1974;58: Benjamin RS, Wiernik PH, Bachur NR. Adriamycin chemotherapy efficacy, safety, and pharmacologic basis of an intermittent single highdosage schedule. Cancer 1974;33: Gurevich I, Akerley W. Treatment of the jaundiced patient with breast car-

13 1082 Chemotherapy Dosing in Organ Dysfunction cinoma. Case report and alternate therapeutic strategies. Cancer 2001;91: Brenner DE, Wiernik PH, Wesley M et al. Acute doxorubicin toxicity. Relationship to pretreatment liver function, response, and pharmacokinetics in patients with acute nonlymphocytic leukemia. Cancer 1984;53: Zanette L, Zucchetti M, Freshi A et al. Pharmacokinetics of 4-demethoxydaunorubicin in cancer patients. Cancer Chemother Pharmacol 1990;30: Camaggi CM, Strocchi E, Carisi P et al. Idarubicin metabolism and pharmacokinetics after intravenous and oral administration in cancer patients: A crossover study. Cancer Chemother Pharmacol 1992;30: Twelves CJ, Dobbs NA, Michael Y et al. Clinical pharmacokinetics of epirubicin: The importance of liver biochemistry Tests. Br J Cancer 1992;66: Dobbs NA, Twelves CJ, Gregory W et al. Epirubicin in patients with liver dysfunction: Development and evaluation of a novel dose modification scheme. Eur J Cancer 2003;39: Ralph LD, Thomson AH, Dobbs NA et al. A population model of epirubicin pharmacokinetics and application to dosage guidelines. Cancer Chemother Pharmacol 2003;52: Hande KR, Wolff SN, Greco FA et al. Etoposide kinetics in patients with obstructive jaundice. J Clin Oncol 1990;8: Arbuck SG, Douglass HO, Crom WR et al. Etoposide pharmacokinetics in patients with normal and abnormal organ function. J Clin Oncol 1986;4: D Incalci M, Rossi C, Zucchetti M et al. Pharmacokinetics of etoposide in patients with abnormal renal and hepatic function. Cancer Res 1986;46: Aita P, Robieux I, Sorio R et al. Pharmacokinetics of oral etoposide in patients with hepatocellular carcinoma. Cancer Chemother Pharmacol 1999; 43: Joel SP, Shah R, Clark PI et al. Predicting etoposide toxicity: Relationship to organ function and protein binding. J Clin Oncol 1996;14: Stewart CF. Use of etoposide in patients with organ dysfunction: Pharmacokinetic and pharmacodynamic considerations. Cancer Chemother Pharmacol 1994;34(suppl):S76 S Raymond E, Boige V, Faivre S et al. Dosage adjustment and pharmacokinetic profile of irinotecan in cancer patients with hepatic dysfunction. J Clin Oncol 2002;20: Venook AP, Enders Klein C, Fleming G et al. A phase I and pharmacokinetic study of irinotecan in patients with hepatic or renal dysfunction or with prior pelvic radiation: CALGB Ann Oncol 2003;14: O Reilly S, Rowinsky E, Slichenmyer W et al. Phase I and pharmacologic studies of topotecan in patients with impaired hepatic function. J Nat Cancer Inst 1996;88: Doroshow JH, Synold TW, Gandara D et al. Pharmacology of oxaliplatin in solid tumor patients with hepatic dysfunction: A preliminary report of the National Cancer Institute Organ Dysfunction Working Group. Semin Oncol 2003;30(suppl 15): Venook AP, Egorin MJ, Rosner GL et al. Phase I and pharmacokinetic trial of gemcitabine in patients with hepatic or renal dysfunction: Cancer and Leukemia Group B J Clin Oncol 2000;18: Desai ZR, Van den Berg HW, Bridges JM et al. Can severe vincristine neurotoxicity be prevented? Cancer Chemother Pharmacol 1982;8: Chong CDK, Logothetis CJ, Savaraj N et al. The correlation of vinblastine pharmacokinetics to toxicity in testicular cancer patients. J Clin Pharmacol 1988;28: Robieux I, Sorio R, Borsatti E et al. Pharmacokinetics of vinorelbine in patients with liver metastases. Clin Pharmacol Ther 1996;59: Panday VR, Huizing MT, Willemse PH et al. Hepatic metabolism of paclitaxel and its impact in patients with altered hepatic function. Semin Oncol 1997;24(suppl 11):S11-34 S Venook AP, Egorin MJ, Rosner GL et al. Phase I and pharmacokinetic trial of paclitaxel in patients with hepatic dysfunction: Cancer and Leukemia Group B J Clin Oncol 1998;16: Francis P et al. Pharmacodynamics of docetaxel in patients with liver metastases. Proc Am Soc Clin Oncol 1994;13: Burris HA. Optimal use of docetaxel (Taxotere): Maximizing its potential. Anticancer Drugs 1996;7(suppl 2): Sanofi-Aventis. Taxotere (docetaxel) [package insert]. Prescribing information as of October Bridgewater, NJ: Sanofi-Aventis, Fleming GF, Schilsky RL, Schumm LP et al. Phase I and pharmacokinetic study of 24-hour infusion 5-fluorouracil and leucovorin in patients with organ dysfunction. Ann Oncol 2003;14: Twelves C, Glynne-Jones R, Cassidy J et al. Effect of hepatic dysfunction due to liver metastases on the pharmacokinetics of capecitabine and its metabolites. Clin Cancer Res 1999;5: Smith GA, Damon LE, Rugo HS et al. High-dose cytarabine dose modification reduces the incidence of neurotoxicity in patients with renal insufficiency. J Clin Oncol 1997;15: Bauer S, Hagen V, Pielken HJ et al. Imatinib mesylate therapy in patients with gastrointestinal stromal tumors and impaired liver function. Anticancer Drugs 2002;13: Eckel F, von Delius S, Dobritz F et al. Pharmacokinetic (PK) and clinical phase II trial of imatinib in patients with impaired liver function and advanced hepatocellular carcinoma (HCC). Proc Am Soc Clin Oncol 2005; 23: Novartis Pharmaceuticals Corporation. Gleevec (imatinib mesylate) [package insert]. Prescribing information as of November East Hanover, NJ: Novartis, Takimoto CH, Liu PY, Lenz H et al. A phase I pharmacokinetic (PK) study of the epothilone B analogue, ixabepilone (BMS ) in patients with advanced malignancies and varying degrees of hepatic impairment. A SWOG Early Therapeutics Committee and NCI Organ Dysfunction Working Group trial. Proc Am Soc Clin Oncol 2006;24: Kintzel PE, Dorr RT. Anticancer drug renal toxicity and elimination: Dosing guidelines for altered renal function. Cancer Treat Rev 1995;21: Joel S, Clark P, Slevin M et al. Renal function and etoposide pharmacokinetics: Is dose modification necessary? Proc Am Soc Clin Oncol 1991;10: Pfluger KH, Hahn M, Holz JB et al. Pharmacokinetics of etoposide: Correlation of pharmacokinetic parameters with clinical conditions. Cancer Chemother Pharmacol 1993;31: Gallo JM, Laub PB, Rowinsky EK et al. Population pharmacokinetic model for topotecan derived from phase I clinical trials. J Clin Oncol 2000;18: GlaxoSmithKline. Hycamtin (topotecan hydrochloride) [package insert]. Prescribing information as of July Philadelphia: GlaxoSmithKline, Takimoto CH, Remick SC, Sharma S et al. Dose-escalating and pharmacological study of oxaliplatin in adult cancer patients with impaired renal function: A National Cancer Institute Organ Dysfunction Working Group study. J Clin Oncol 2003;21: Takimoto CH, Remick SC, Sharma S et al. Administration of oxaliplatin to