Chemotherapy in chronic kidney disease and dialysis

Mechlorethamine (nitrogen mustard)

Mechlorethamine is the prototype anticancer chemotherapeutic drug. Successful clinical use of mechlorethamine gave birth to the field of anticancer chemotherapy. It is used mostly in Hodgkins lymphoma and as palliative treatment for malignant effusions of metastatic carcinomas. The dosage is based on ideal dry weight and the drug is rapidly metabolized with minimal urinary excretion, hence no adjustment is needed in kidney failure. There are no data available regarding its use in hemodialysis (HD) or in peritoneal dialysis (PD).

Cyclophosphamide

The oxazaphosphorine alkylating agent, cyclophosphamide, is used across a wide range of tumor types and was introduced to clinical practice in 1958. The drug may be administered either parenterally or orally. Systemic availability after oral administration is greater than 75%. Cyclophosphamide is inactive until it undergoes hepatic transformation to form 4-hydroxycyclophosphamide, which then breaks down to form the ultimate alkylating agent, phosphoramide mustard and other inactive products. The drug is minimally protein bound but some of its metabolites are more than 60% protein bound. The metabolites and up to 25% of the unchanged parent compound are ultimately eliminated by the kidneys. ^, Pharmacokinetics studies of cyclophosphamide in kidney failure have yielded conflicting results. Some authors have not found any alterations in the presence of hepatic or renal insufficiency, ^, leading them to not recommend any adjustment of the dose in the presence of kidney failure, whereas others have reported a significantly decreased clearance of the drug in the presence of severe renal insufficiency. ^, Myelosuppression is usually the dose-limiting toxicity; however, in the setting of bone marrow transplantation, escalation beyond that dosage range is limited by cardiac toxicity. Synergistic hematopoietic toxicity may occur with concomitant use of allopurinol. Both unchanged cyclophosphamide and its metabolites are extensively cleared by HD. For optimal dosing, the use and timing of HD should be considered. There are no data in PD.

Ifosfamide

Ifosfamide, an isomer of cyclophosphamide, is extensively used in the treatment of solid tumors in children and in soft tissue sarcoma. Other indications include refractory germ cell cancer, as a third-line agent, ^, osteosarcoma, bladder cancer, small cell lung cancer, cervical cancer, ovarian cancer, and non-Hodgkin lymphoma. Like cyclophosphamide, it should be coadministered with 2-mercaptoethane sulfonate sodium (MESNA) to prevent hemorrhagic cystitis. It is extensively metabolized, principally in the liver, to active and inactive metabolites and principally excreted in the urine. The terminal half-life is 4 to 8 hours on average in adults. The drug itself is not directly toxic to the kidney, but its metabolite chloracetaldehyde, has been shown to be toxic to renal tubular cells in vitro and in vivo. Both acute and reversible kidney damage along with chronic toxicity may develop. Proximal tubular dysfunction is the commonest presentation, and may lead to a Fanconi syndrome, including hypophosphataemic rickets and proximal renal tubular acidosis (RTA). Other manifestations include distal RTA and nephrogenic diabetes insipidus. Younger age at exposure and cumulative ifosfamide dose are considered the major determinants of nephrotoxicity. ^, Nephrotoxicity is also associated with previous or concurrent cisplatin therapy along with preexisting kidney impairment. ^, Neurotoxicity is another major side effect that is increased in patients with compromised kidney function and is characterized by confusion, auditory and/or visual hallucinations, mutism, and encephalopathy, which may progress to stupor and coma. Despite the lack of pharmacokinetic data, in a small case series, ifosfamide use in HD has been shown to be feasible. Dose could be adjusted based on degree of myelosuppression and neurotoxicity. In vitro studies suggest that HD can decrease ifosfamide concentrations by 87% and chloracetaldehyde by 77% and HD has been used to treat ifosfamide toxicity. There are no data about its use in PD.

Melphalan

Melphalan was synthesized in 1953, and it has been an important therapy for multiple myeloma (MM) for 50 years despite the introduction of many novel agents. It acts both as cytotoxic agent through damage to deoxyribonucleic acid, and as immunostimulatory drug by inhibiting interleukin-6, as well as interacting with dendritic cells, and immunogenic effects in tumor microenvironment. The absorption of melphalan is incomplete and prone to large interindividual variations, leading to a poorly predictable response. It is eliminated renally and the kidney function has an effect on its pharmacokinetics with an increased median half-life (t1/2) and area under the concentration curve (AUC) when creatinine clearance (CrCl) is less than 40 mL/min. Hence a dose reduction of 25% has been recommended for patients with CrCl between 10 and 40 mL/min and a further reduction to 50% if the clearance is less than 10 mL/min. However, high unadjusted melphalan doses followed by stem cell transplantation has been safely used in patients on HD. ^, There are no data regarding its use in PD ( Table 19.1 ).

Chlorambucil

Chlorambucil is mostly used to treat chronic lymphocytic leukemia (CLL) but also Hodgkin and non-Hodgkin lymphoma, breast, ovarian and testicular cancers, Waldenstrom macroglobulinemia, and choriocarcinoma. It is well absorbed orally and is metabolized by a microsomal β-oxidation process to phenylacetic acid mustard, which by itself has antineoplastic activity. Less than 1% of both the unchanged drug and its phenylacetic acid metabolite are excreted unchanged in the urine. Hence dosage reduction is not recommended in renal failure, even if some authors have advocated reducing the dose by 50% if the CrCl is less than 50 mL/min and by 75% if it is less than 10 mL/min. The dose should also be reduced by 50% in PD.

Altretamine (hexamethylmelamine)

Altretamine undergoes rapid hepatic metabolism and less than 1% of the drug is retrieved in the urine 24 hours after administration. ^, Hence no dose reduction is necessary in renal failure. There are no data about its use in HD or PD.

Thiotepa

Thiotepa is rapidly metabolized by cytochrome P450 to triethylene phosphoramide (TEPA), which is the main and active metabolite with similar alkylating properties. Less than 2% of the administered dose of thiotepa is eliminated unchanged in the urine. Elimination of TEPA by the kidneys accounts for approximately 11% of the administered dose. ^, Many experts recommend no dosage adjustment in kidney failure; however, a pharmacokinetics study done in a patient with moderate renal insufficiency showed increased exposure to thiotepa and especially TEPA with subsequent toxicity, leading the authors to recommend reduced dosing in similar cases. There are no data available about its use in HD or PD.

Busulfan

Busulfan is an alkylating agent used primarily in hematologic malignances as a preparative regimen before hematopoietic stem cell transplantation (HSCT). Busulfan is primarily eliminated by conjugation with glutathione, and less than 2% of an oral dose is eliminated unchanged in the urine and dose reduction is usually not necessary in renal failure. Busulfan is effectively removed by HD but according to a report, a standard HD period (i.e., 4 hours) does not significantly affect busulfan apparent clearance. There are no data regarding the use of busulfan in PD.

Carmustine, lomustine, and semustine

Carmustine (BCNU), lomustine (CCNU), and semustine (methyl-CCNU) cross the blood-brain barrier and are mostly used for the treatment of gliomas. Urinary excretion of BCNU, CCNU, and methyl-CCNU is significant with 43%, 50%, and 47% of the drugs, respectively, retrieved in the urine 24 hours following drug administration. ^, Dose adjustment is recommended in kidney failure. For BCNU, it has been recommended to administer 80% of the dose if the CrCl is less than 60 mL/min, 75% if the CrCl is less than 45 mL/min, and to avoid its use for a CrCl of less than 30 mL/min. For CCNU, the dose should be reduced by 25% if the CrCl is less than 60 mL/min and by 50% if the CrCl is less than 45 mL/min. The drug should also be avoided if the CrCl is less than 30 mL/min. No formal recommendations exist for methyl-CCNU, but likely the same dose reductions apply. BCNU is not dialyzable; however, there have been documented cases when BCNU was used with a dose reduction in patients on HD with the doses escalated and reduced depending on white cell count. There is no documentation of its use in PD. Moreover, there is no documentation about the use of either CCNU or methyl-CCNU in HD or PD.

Streptozocin

Streptozocin is active against pancreatic neuroendocrine tumors and pancreatic adenocarcinomas. Only 15% to 20% of streptozocin is excreted in the urine. ^, It has been recommended to reduce the dose by 25% for a CrCl of less than 50 mL/min and by 50% for a CrCl of less than 10 mL/min. However, the drug is known to have a dose-related nephrotoxic effect and to induce Fanconi syndrome. ^, It might be advisable to avoid it in the setting of advanced renal failure or deteriorating renal function. There are no reports of its use in HD or PD.

Dacarbazine

Dacarbazine (DTIC) is a cell cycle nonspecific antineoplastic alkylating agent used in the treatment of metastatic malignant melanoma and Hodgkin lymphoma. Up to 40% of the drug is excreted unchanged in the urine through tubular secretion. It has been recommended to decrease the dose by 25% for a CrCl of less than 60 mL/min, to administer 50% of the dose for a CrCl between 10 and 30 mL/min, and to avoid with CrCl less than 10 mL/min. DTIC is dialyzable and has been safely used in HD.

There is no report of use in PD.

Temozolomide

Temozolomide (TMZ) is used for the treatment of brain tumors and melanoma. The most important factor influencing the clearance of TMZ is body surface area (BSA) with increased BSA associated with increased clearance and clearance by the kidneys playing an insignificant role. TMZ has been safely administered in HD at full dose. There is no reported use in PD.