Oral Chemotherapeutic Agents in Patients with Renal Dysfunction

Oral chemotherapeutic agents have transformed the management of cancer treatment— transitioning the primary location of care to the ambulatory setting and providing patients with a convenient, noninvasive option to manage their malignancy. Despite the growing availability of oral chemotherapeutic agents, data describing the management of these agents in patients with renal dysfunction are limited.

Renal dysfunction represents one of the most important contributors to drug accumulation, which may manifest as mild to severe adverse effects. Dose reductions are often necessary to prevent the accumulation of renally metabolized and/or eliminated drugs to prevent toxicities, such as prolonged myelosuppression, mucositis, peripheral neuropathies, or central neurotoxicities.^1,2 Treatment goals should be considered carefully, because they may influence the clinical decision of proceeding with a more aggressive dose or pursuing a reduced dose for palliative purposes.

The following review presents the available data to help guide the management of oral chemotherapeutic agents in patients with renal dysfunction. Based on the information provided, dose adjustment recommendations in renally compromised patients have been summarized in the Table.

Figure 1

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Capecitabine

5-Fluorouracil (5-FU) is a pyrimidine analog with antitumor activity against a wide variety of solid tumors, such as colorectal, esophageal, gastric, bladder, and breast.³ Capecitabine, an oral prodrug of 5-FU, exhibits nearly 100% bioavailability and is activated preferentially in tumor cells. After absorption through the gastrointestinal tract, capecitabine under goes hepatic metabolism to generate 5′-deoxy-5-fluorocytidine and 5′-deoxy-5-fluorouridine (5′-DFUR). Ultimately, 5′-DFUR is converted to 5-FU by the enzyme thymidine phosphorylase, which is found in both normal and tumor tissues. Thymidine phosphorylase concentrations, however, are 3 to 10 times higher in solid tumors than in normal tissues, which theoretically allows for preferential activation and fewer systemic toxicities, such as diarrhea, hand–foot syndrome, and neutropenia.⁴

Capecitabine and its metabolites are eliminated in the urine, with mean urinary recovery between 71% and 87%.⁵ Renal impairment, therefore, may lead to an increase in the systemic exposure to certain metabolites; dosing at 75% of the standard dose is recommended in patients with moderate renal impairment (baseline creatinine clearance [CrCl] 30-50 mL/min).⁶ In addition, capecitabine is contraindicated in patients with severe renal impairment (CrCl <30 mL/min).⁷

Cyclophosphamide

Cyclophosphamide, a nitrogen mustard alkylating agent, exerts its antineoplastic effects by binding to the N7 position of guanine to create intra- and interstrand DNA cross-linkages.⁸ Cyclophosphamide has been used to treat a wide variety of oncologic diseases, such as Hodgkin and non-Hodgkin lymphomas, acute and chronic leukemias, as well as breast, ovarian, and testicular cancers.³ In addition, cyclo phosphamide possesses potent immunosuppressive activity and may be used to treat various nonneoplastic autoimmune disorders where diseasemodifying antiinflammatory drugs have been ineffective, such as refractory nephritic syndrome in children. Oral cyclophosphamide is well absorbed, usually nearing complete absorption.^8,9

As a prodrug, cyclophosphamide re quires hepatic activation via CYP2B6, CYP2C9, and CYP3A4 to generate a 4- hydroxycyclophosphamide intermediate that exists in equilibrium with aldophosphamide. The spontaneous cleavage of aldophosphamide generates the cytotoxic component phosphoramide mustard and the urotoxic metabolite, acrolein.⁸ Although cyclo phosphamide and its metabolites are eliminated in the urine (5%-25% as unchanged drug), no consistent evidence indicate dose modifications in renally compromised patients.^8,10,11 Aronoff and colleagues recommend a 25% dose reduction in patients with a glomerular filtration rate <10 mL/min.¹²

Etoposide

Since its introduction in 1971, etoposide has been used to treat a variety of cancers, such as lung, testicular, breast, bone (Ewing sarcoma, osteosarcoma), ovarian, esophageal, and gastric, as well as leukemias and lymphomas.³ Al though etoposide is a semisynthetic podophyllotoxin derivative, it exerts its antineoplastic effects as a topoisomerase II inhibitor by forming a ternary complex with DNA and topoisomerase II to prevent the religation of DNA strands.¹³ Because etoposide is cell-cycle-phase–specific, activity is best achieved when administered in divided doses over multiple days rather than in large single doses.¹³Oral bioavailability of etoposide capsules appears to be linear and ranges from 25% to 75%, with mean bioavailability of 50%.¹⁴ Etoposide and its metabolites are primarily eliminated via renal clearance, which accounts for 44% to 60% of plasma clearance (67% as un changed drug).¹⁵

Multiple studies have correlated decreased renal function with decreased etoposide systemic clearance, which suggests that doses should be reduced in elderly patients and/or patients with impaired renal function.^16-19 Pflüger and colleagues evaluated the pharmacokinetic parameters of etoposide in 35 patients, which demonstrated that renal impairment resulted in increased terminal elimination half-life and area under the curve (AUC) as well as decreased volume of distribution at steady state and systemic clearance of etoposide.¹⁶ Kintzel and Dorr recommend a 15% dose reduction for CrCl 46 mL/min to 60 mL/min, 20% for CrCl 31 mL/min to 45 mL/min, and 25% for CrCl ≤30 mL/min^.20 In terestingly, etoposide also is cleared via nonrenal processes, such as metabolism and biliary excretion; thus, there is a potential for compensatory elimination in patients with impaired hepatic and/or renal function.^14,18

Hydroxyurea

Hydroxyurea produces antineoplastic effects by interfering with ribonucleotide reductase to cause “immediate inhibition of DNA synthesis.”²¹ In doing so, significant tumor response to hydroxyurea has been demonstrated in melanoma; refractory chronic myelogenous leukemia; recurrent, metastatic, or inoperable ovarian cancer; and squamous cell head and neck cancer.³ In addition, hydroxyurea concentrates in erythrocytes and leukocytes and is used widely for adjunctive management of sickle cell disease, rapid reduction of white blood cell count in patients with elevated blast counts or leukostasis, and supportive care induction therapy in acute myeloid leukemia patients aged 60 years or older with poor performance status or significant comorbidities.^3,21

Hydroxyurea was found to be 79% bioavailable in cancer patients following oral administration and eliminated via renal and nonrenal mechanisms as unchanged drug, urea, and other metabolites.^21-23 Renal clearance of hydroxyurea is approximately 75% of the glomerular filtration rate, which suggests that hydroxyurea should be reduced when used in patients with renal impairment. In their summary, Kintzel and Dorr provided dose reduction recommendations for hydroxyurea: 15% for CrCl 46 mL/min to 60 mL/min, 20% for CrCl 31 mL/min to 45 mL/min, and 25% for CrCl ≤30 mL/min.²⁰ Aronoff and colleagues recommended an 80% dose reduction for CrCl <10 mL/min.¹² In general, the use of hydroxyurea requires close supervision and doses should be titrated based on the patient’s response and white blood cell count.

Imatinib

Imatinib and related tyrosine kinase inhibitors (TKIs) target the BCR-ABL oncogene, a constitutively activated protein kinase that resulted from the fusion of the Abelson proto-oncogene on chromosome 9 with the breakpoint cluster region on chromosome 22.²⁴ In addition, imatinib inhibits tyrosine kinase receptors for c-KIT, which is often associated with gastrointestinal stromal tumors (GISTs), as well as platelet-derived growth factor, which is often associated with hypereosinophilic syndrome.^3,24-26 All TKIs are predominantly metabolized by CYP3A4, with minor assistance from other pathways and eliminated in the feces.²⁵

Although renal elimination plays a minor role in the elimination of imatinib, renal impairment can have a noticeable effect on imatinib pharmacokinetics, increasing the mean AUC by 1.5- to 2-fold compared with patients with normal renal function.^27,28 The manufacturer recommends maximum doses of 600 mg and 400 mg in patients with CrCl 40 mL/min to 59 mL/min and CrCl 20 mL/min to 39 mL/min, respectively.²⁸ In a phase 1 study conducted in 60 adult patients with varying renal function, imatinib exposure was significantly greater and serious adverse events were significantly more common in the mild-to-severe renal dysfunction groups than in the normal group. Despite having increased imatinib exposure, daily imatinib doses up to 800 mg were generally well tolerated in the mild-to-moderate group.²⁷

Lenalidomide

Lenalidomide is an immunomodulatory analog of thalidomide with antiangiogenic and antineoplastic properties.¹³ It is indicated for the treatment of patients with transfusion-dependent myelodysplastic syndrome (MDS) with or without deletion 5q cytogenetic abnormality and in combination with dexamethasone for multiple myeloma.²⁹ Lenalidomide is absorbed rapidly from the gastrointestinal tract and approxi- mately 67% is eliminated in the urine as unchanged drug. In patients with moderate- to-severe renal function, the drug has an increased half-life, increased AUC, and decreased clearance.²⁹ Thus, dose adjustments are required in patients with abnormal renal function to prevent unnecessary toxicities.

In a retrospective analysis to assess the impact on safety and efficacy of lenalidomide in patients with varying degrees of renal dysfunction, Dimopoulos and colleagues found that patients with renal insufficiency experienced an increased incidence of thrombocytopenia and more often required lenalidomide dose reduction or interruptions. ³⁰ In a separate, prospective analysis of 50 patients treated with lenalidomide, Dimopoulos and colleagues concluded that lenalidomide could be administered without excessive toxicities at doses adjusted according to renal function.³¹ The following dose adjustments are recommended for patients with multiple myeloma: 10 mg daily for CrCl 30 mL/min to 60 mL/min, 15 mg every other day for CrCl <30 mL/min (nondialysis patients), 5 mg daily or 15 mg 3 times per week for CrCl <30 mL/min (following dialysis on dialysis days).^29,31 In addition, the following dose adjustments are recommended for patients using lenalidomide for treatment of MDS: 5 mg daily for CrCl 30 mL/min to 60 mL/min, 5 mg every other day for CrCl <30 mL/min (nondialysis patients), and 5 mg 3 times weekly for CrCl <30 mL/min (following dialysis).²⁹

Melphalan

Like other nitrogen mustard alkylating agents, melphalan exerts its cytotoxic activity by binding to the N7 position of guanine to create intra- and interstrand DNA cross-linkages.^13,32 Melphalan tablets are indicated for the palliative treatment of multiple myeloma as well as nonresectable epithelial carcinoma of the ovary.³ Melphalan is generally reserved for nontransplant candidates because long-term treatment with alkylating agents damages the bone marrow and may make stem cell harvest and autologous transplant difficult.³³ Oral absorption of melphalan is highly variable and incomplete, with average absolute bioavailability ranging from 56% to 93%.^9,32 Melphalan is primarily eliminated from the plasma via chemical hydrolysis but also is partially eliminated in the urine (~10%).^9,32

Multiple pharmacokinetic studies have demonstrated the effects of impaired renal function on plasma melphalan elimination, AUC, and mean residence time, all which suggest the need for dose adjustments in patients with impaired renal function.^20,34 However, because oral absorption of melphalan is incomplete and highly unpredictable, limited data regarding recommendations for dose adjustments currently exist for oral melphalan.³² In a retrospective analysis in multiple myeloma patients with renal failure, Carlson and colleagues suggest a 25% dose reduction for CrCl <30 mL/min. Unfortunately, less than 2% of their study patients had CrCl ≤10 mL/min; therefore, no further recommendations could be provided.³⁵

Methotrexate

Methotrexate inhibits DNA synthesis, repair, and cellular replication by binding to the active catalytic site of dihydrofolate reductase (DHFR).³⁶ DHFR is needed to convert dihydrofolate to tetrahydrofolate, the active form of folic acid needed in the synthesis of purine nucleotides and thymidylate.^13,26 Patients may be at risk of developing methotrexate toxicity for a variety of reasons, some of which include impaired renal function (which in turn can delay methotrexate clearance); presence of pleural or peritoneal effusions or other third spacing (which in turn acts as a reservoir for methotrexate); and concomitant administration with interacting medications, such as penicillin, trimethoprim-sulfamethoxazole, proton pump inhibitors, nonsteroidal antiinflammatory drugs, and organic acids. Delayed methotrexate elimination may lead to serious adverse effects, such as myelosuppression, nephrotoxicity, hepatotoxicity, mucositis, sepsis, and death.³⁶ Approximately 80% of methotrexate is eliminated in the urine as active or toxic moiety (range, 51%-89%).^20,37,38 Thus, methotrexate doses should be reduced in patients with severe renal impairment to avoid potential toxicities. Kintzel and Dorr recommended a 35% dose reduction in patients with CrCl 46 mL/min to 60 mL/min and a 50% dose reduction in patients with CrCl 31 mL/min to 45 mL/min.²⁰ In addition, use should be avoided in patients with CrCl <10 mL/min.

Procarbazine

The exact mechanism of procarbazine is largely undefined but is thought to involve the methylation of the N7 position of guanine of transfer RNA (tRNA).³⁹ By inhibiting the synthesis of tRNA, procarbazine ultimately interferes with proper protein, DNA, and RNA syntheses.^26,40 Procarbazine originally was indicated for stage III and IV Hodgkin lymphoma as part of the mechlorethamine/vincristine/procarbazine/ prednisone (MOPP) regimen. ³⁹ However, because of significant and undue long-term toxicities, MOPP largely has been replaced with alternative regimens. Procarbazine also may be used in combination with other antineoplastic agents to treat non-Hodgkin lymphoma and central nervous system malignancies.³

Oral absorption of procarbazine is rapid, complete, and largely comparable with intravenous administration. ^26,39,40 Procarbazine, however, requires activation via hepatic and mitochrondrial activity, most of which occurs during first-pass metabolism following absorption from the gastrointestinal tract, to form azoprocarbazine, the major circulating metabolite, and benzylazoxy and methylazoxy intermediates. ^26,39,41-43 These 2 intermediates are metabolized further to produce N-isopropylterepthalamic acid, an inactive metabolite that is excreted in the urine; and methyldiazonium, the major cytotoxic metabolite, respectively.^26,39,41-43 Following a radiolabeled dose of procarbazine, approximately 70% of radioactivity was recovered in the urine as N-isopropylterepthalamic acid.^39,44 Although procarbazine largely is eliminated in the urine as inactive metabolites, caution should be exercised in patients with impaired renal and/or hepatic function.³⁹ No dosing recommendations are currently available.

Sorafenib

Similar to other members of the TKI class, sorafenib inhibits multiple intracellular and cell surface kinases to inhibit tumor growth and angiogenesis. ⁴⁵ Significant tumor response to sorafenib has been demonstrated in unresectable liver carcinoma, advanced renal cell carcinoma, angiosarcoma, GIST, and thyroid carcinomas.³ Oral bioavailability of sorafenib is 38% to 49% and achieves peak plasma levels approximately 3 hours after administration.45 Sorafenib undergoes significant hepatic metabolism by CYP3A4 and is also glucuronidated by uridine diphosphate glucuronosyltransferase (UGT) 1A9.^25,45 In a prospective study of 138 treated patients, sorafenib pharmacokinetics were characterized to determine tolerable starting doses in patients with hepatic and/or renal impairment: 400 mg twice daily for CrCl ≥40 mL/min, 200 mg twice daily for CrCl 20 mL/min to 39 mL/min, and 200 mg daily in patients on hemodialysis.⁴⁶

Conclusion

Renal dysfunction is an important contributor to the accumulation of antineoplastic agents and may lead to severe adverse effects, such as bone marrow suppression, mucositis, end-organ damage, and death. Dose reductions are often necessary to prevent such adverse effects but may be complicated by the balance between “sufficient efficacy and acceptable toxicity.”¹ In most cases, dose escalations may be made after it is determined that the patient was able to tolerate the previous dose. 

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