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The Oncologist, Vol. 12, No. 9, 1070-1083, September 2007; doi:10.1634/theoncologist.12-9-1070
© 2007 AlphaMed Press

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 Commentary: Oncologic Drugs in Patients with Organ Dysfunction: A Summary
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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

Correspondence: 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: 916-734-3771; Fax: 916-734-7946; e-mail: angela.davies{at}ucdmc.ucdavis.edu

Received January 4, 2007; accepted for publication June 26, 2007.

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
Top
 Learning Objectives
Abstract
 Introduction
 Hepatic Dysfunction
 Renal Dysfunction
 Conclusions
 References
 
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.

Access and take the CME test online and receive 1 AMA PRA Category 1 CreditTM at CME.TheOncologist.com


   ABSTRACT
Top
 Learning Objectives
 Abstract
Introduction
 Hepatic Dysfunction
 Renal Dysfunction
 Conclusions
 References
 
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.


   INTRODUCTION
Top
 Learning Objectives
 Abstract
 Introduction
Hepatic Dysfunction
 Renal Dysfunction
 Conclusions
 References
 
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 estimate of renal elimination, using measured or calculated creatinine clearance (CrCL): Dose (mg) = (CrCL + 25) (ml/minute) x 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 1Go). 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.


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  		Table 1. Metabolism and excretion of commonly used chemotherapeutic agents

 


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  		Table 1. (Continued)

 
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
Top
 Learning Objectives
 Abstract
 Introduction
 Hepatic Dysfunction
Renal Dysfunction
 Conclusions
 References
 
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].


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  		Table 2. Modified Child-Pugh score

 
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 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 >3x 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 ≤2x 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 dysfunction (serum bilirubin 1.5–2x ULN, gamma-glutamyl transferase 2–8x ULN, and alkaline phosphatase [ALP] 1.5–6x ULN) demonstrated no PK alteration or greater toxicity [11]. Using a slightly different definition of mild-to-moderate liver dysfunction (AST 1.5–4x ULN, ALT 1.5–8x ULN, and ALP 1.5–2x 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 3GoGo).


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  		Table 3. Recommended dose adjustment for liver and kidney dysfunction

 


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  		Table 3. (Continued)

 


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  		Table 3. (Continued)

 
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 1.5–3x ULN required a dose reduction from 350 mg/m2 to 200 mg/m2 every 3 weeks to prevent severe toxicity [22]. Venook et al. [23] evaluated four treatment cohorts: (a) AST ≥3x ULN and direct bilirubin <1 mg/dl, (b) direct bilirubin 1–7 mg/dl, (c) creatinine 1.6–5 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 1.7–4.9 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 (1.7–5.7 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/m2, and subsequently be given escalating doses if the therapy is tolerated [26].

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 1.5–3 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 2x ULN and bilirubin <1.5 mg/dl, (b) bilirubin 1.6–3 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 >50–75 mg/m2 were not tolerated by patients with liver dysfunction. For the 3-hour infusion, doses of 100 mg/m2 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/m2 [31].

Docetaxel
Dose reduction is also recommended for docetaxel in patients with liver dysfunction because of the higher risk for neutropenia, mucositis, and treatment-related death [32, 33]. Some authors have recommended omitting the drug for patients with serum bilirubin >1x ULN or AST/ALT >1.5x ULN concomitant with ALP >2.5x 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 1.5–3 mg/dl), mild-to-moderate hepatic dysfunction (serum bilirubin 1.5–5 mg/dl), and moderate-to-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 {alpha}-fluoro-ß-alanine. Twelves et al. [36] found that mild-to-moderate hepatic dysfunction (mean bilirubin, 6.5 mg/dl; range, 0.9–28.3 mg/dl) had no clinical significance on the PKs of capecitabine. No data 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 3GoGo) [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/m2 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 1.5–1.6 higher AUC. Thus, they determined that a 50% dose reduction was required for patients with bilirubin levels 1.5–3x ULN because of greater toxicity. In the setting of mild hepatic impairment, further recommendations are pending [41].


   RENAL DYSFUNCTION
Top
 Learning Objectives
 Abstract
 Introduction
 Hepatic Dysfunction
 Renal Dysfunction
Conclusions
 References
 
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 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 1.73m2) 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 ≥3x ULN and direct bilirubin <1 mg/dl, (b) direct bilirubin 1–7 mg/dl, (c) creatinine 1.6–5 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 20–39 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/m2 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 1.6–3.2 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 1.5–3 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 30–50 ml/minute) required 5-FU dose reductions because of grade 3 or 4 treatment-related toxicities, 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 {alpha}-fluoro-ß-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 30–50 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 1.5–1.9 mg/dl or an increase in creatinine during treatment of 0.5–1.2 mg/dl, the cytarabine dose was reduced from 2–3 g/m2 per day to 1 g/m2 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/m2 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 46–60 ml/minute and a 50% reduction for a CrCL of 31–45 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 46–60 ml/min, a 25% reduction for a CrCL of 31–45 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 40–50 ml/minute, a dose reduction to 70%; (b) for a CrCL of 30–40 ml/minute, a reduction to 60%; (c) for a CrCL of 20–30 ml/minute, a reduction to 52%; and (d) for a CrCL of 10–20 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/m2, 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 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/m2 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, 51–80 ml/minute, and ≤50 ml/minute). All groups of patients had similar rates of discontinuation and similar adverse event profiles.


   CONCLUSIONS
Top
 Learning Objectives
 Abstract
 Introduction
 Hepatic Dysfunction
 Renal Dysfunction
 Conclusions
References
 
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 3GoGo.


   REFERENCES
Top
 Learning Objectives
 Abstract
 Introduction
 Hepatic Dysfunction
 Renal Dysfunction
 Conclusions
 References
 

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