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Keywords:

  • abbreviated Modification of Diet in Renal Disease formula;
  • Cockcroft-Gault formula;
  • creatinine clearance;
  • renal insufficiency;
  • serum creatinine;
  • solid tumors

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

BACKGROUND.

The Renal Insufficiency and Cancer Medications (IRMA) study is a French national observational study. The results from this study of nearly 5000 patients demonstrated the high prevalence of renal impairment in a population of patients with solid tumors.

METHODS.

Every cancer patient who presented at oncology departments that participated in the study over at least 1 of 2 predefined periods during 2004 were included. Renal function was calculated using Cockcroft-Gault and abbreviated Modification of Diet in Renal Disease (aMDRD) formulae to estimate the prevalence of renal insufficiency (RI) according to the Kidney Disease Outcomes Quality Initiative-Kidney Disease Improving Global Outcomes definition and stratification. Anticancer drugs were studied with regard to their potential renal toxicity and dosage adjustment.

RESULTS.

Of the 4684 patients from the 15 centers, 7.2% had serum creatinine levels >110 μmol/L. However, when they were assessed using Cockcroft-Gault and aMDRD formulae, 57.4% and 52.9% of patients had abnormal renal function or RI, respectively. Of the 7181 anticancer drug prescriptions, 53.4% required dose adjustments for RI. Of the patients treated, 79.9% received at least 1 such drug. And 80.1% received potentially nephrotoxic drugs.

CONCLUSIONS.

RI was common in patients with cancer, and drug dosage adjustments often were necessary. Renal function should be evaluated in all cancer patients using either the Cockcroft-Gault formula or the aMDRD formula, including patients with normal serum creatinine levels. In patients who are at high risk for drug toxicity, the dosage should be adapted to renal function, and the use of nephrotoxic therapies should be avoided whenever possible. Cancer 2007. © 2007 American Cancer Society.

The increased incidence of malignancies in patients with chronic renal failure has been discussed since the middle 1970s.1, 2 In a recent study, Cengiz reported that 188 organ tumors (6.7%) of various pathologies were identified in 2817 patients who had chronic renal failure.3 Although it is known as a common pathology in the general population,4 currently, the incidence of renal insufficiency (RI) among patients with cancer remains unclear. Only limited data are available. In a pilot study,5 we observed a high prevalence of RI of approximately 33% among 316 patients from 2 anticancer centers. Only 9.2% of those patients had elevated serum creatinine (SCR) levels, but 33% had a creatinine clearance (CrCl) <80 mL per minute, the upper limit of normal at the time of this study (before the Kidney Disease Outcomes Quality Initiative [K/DOQI]-Kidney Disease Improving Global Outcomes [KDIGO] official international definition of RI). More recently, Dogan and colleagues6 studied the frequency of abnormal renal function calculated with the Cockcroft-Gault method compared with SCR screening in a population of 1217 patients with cancer. RI was defined as a CrCl <90 mL per minute, as recommended by the K/DOQI. Among those patients, 5.9% had elevated SCR levels (>1.2 mg/dL, which corresponds to approximately 106 μmol/L), but 27.1% had RI calculated with the Cockcroft-Gault formula.

The findings of our pilot study and of the smaller cohort study of Dogan et al. emphasize the high incidence of RI in cancer patients. This is an important issue in clinical practice for the handling of anticancer drugs in those patients. Because approximately 50% of all anticancer drugs are excreted predominantly in the urine as unchanged drug or active metabolite(s), any reduction in renal clearance results in accumulation of potentially toxic species and overdosage. The dosage of chemotherapeutic agents used in these patients with RI, thus, frequently will require dosage reduction to avoid severe toxicities. Furthermore, using potentially nephrotoxic anticancer drugs also will require specific monitoring and, when available, specific prevention methods to help reduce the risk for renal toxicity, especially in patients who already have abnormal renal function.

In this report, we present results from the Renal Insufficiency and Anticancer Medications (IRMA) study, a large, national cohort, multicentric, retrospective, observational study that was conducted to assess the prevalence of RI in cancer patients. The objective of this study also was to describe the profile of the anticancer drugs prescribed to those patients regarding the need for dosage adjustment and potential for nephrotoxicity. This study was not designed to identify the potential causes of renal function abnormalities observed in our patients. The 2 questions that we sought to answer were: 1) Are patients with cancer frequently presenting with abnormal renal function; and 2) do the anticancer drugs prescribed need dosage adjustment in such patients, and do they represent further potential renal toxicity?

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

Study Population

The IRMA study included a total of 4684 patients who were being treated for solid tumors (either in hospital or as outpatients) in an oncology department. The study consisted of retrospective patient data collection on 1 of 2, specific, 15-day periods between either February 1 and February 15, 2004 or October 1 and October 15, 2004. These periods were selected to avoid summer vacations and to be representative of the whole year, with 1 period in winter/spring and the other period in fall/winter.

Patients were included regardless of disease pathology, treatment (antineoplastic drugs used/to be used, pretreated or not pretreated). Patients were excluded if they were aged <18 years, had a diagnosis of myeloma, or presented with end-stage renal disease that required renal replacement therapy (either hemodialysis or peritoneal dialysis).

Study Design and Assessments

The objectives of this national, retrospective study were to investigate the prevalence of RI in cancer patients in France and to characterize anticancer drugs that were prescribed to the study population, with particular emphasis on their potential interactions with the kidney, ie, potential renal toxicity, and/or the need for dosage adjustment in patients with RI.

The following data were collected for each patient: sex, age, weight, SCR, blood urea nitrogen, hemoglobinemia, type of tumor, metastasis, and anticancer drugs prescribed. The upper limit of the SCR at the Pitie-Salpetriere central laboratory was 110 μmol/L during the time this study was in progress. Patients who were known to present with acute renal failure were excluded to determine the prevalence of potentially chronic abnormal renal function. Estimations of renal function were made by calculating the CrCl or the Glomerular Filtration Rate (GFR) using the Cockcroft-Gault formula7 and the abbreviated Modification of Diet in Renal Disease (aMDRD) formula.8

Cockcroft-Gault formula
  • equation image

where k = 1.23 (male) or 1.04 (female).

aMDRD formula
  • equation image

where k = 1 (men) or 0.742 (women), GFR indicates glomerular filtration rate, and SCR is measured in mg/dL.

Renal function, which was calculated using either formula, was staged in accordance with the clinical practice guidelines published by the Working Group of the National Kidney Foundation,9 as follows:

  • Stage 1, GFR ≥90 mL per minute;

  • Stage 2, GFR from 60 to 89 mL per minute;

  • Stage 3, GFR from 30 to 59 mL per minute;

  • Stage 4, GFR from 15 to 29 mL per minute; and

  • Stage 5, GFR <15 mL per minute.

With regard to anticancer therapies prescribed to study patients, those drugs that required dosage adjustment were identified in accordance with their pharmacokinetics and available recommendations from both their individual Summary of Product Characteristics (SmPC) and from 2 reference books. In a previous study,5 the Vidal Dictionary10 and the Physicians Desk Reference11 were used to provide information on dosing adjustments; however, it was demonstrated that these references did not provide the necessary information. Therefore, we used 2 specific reference books on drug dosage adjustment in patients with RI: Drug Prescribing in Renal Failure: Dosing Guidelines for Adults, 4th edition,12 and the Guide to Prescription Medications for Patients with Renal Insufficiency, third edition.13 Then, anticancer medications were classified as “yes” when adjustment was required, “no” when adjustment was not necessary, and “no data” when no data were available in the literature.

To obtain profiles of anticancer therapies with regard to renal tolerance, an exhaustive literature search was performed using the National Institutes of Health PubMed14 data base to identify any potential renal side effects of the therapies. If, at least some episodes of nephrotoxicity were identified in the literature search, then the therapy was classified as “yes,” which indicated that the drug was “potentially nephrotoxic.” Therapies were labeled “no” when no such episodes were identified or when there were no suggestions of potential renal toxicity.

Of course, coprescriptions, such as nonsteroidal antiinflammatory drugs, may be a concern in such patients with potential abnormal renal function at baseline. However, information on such coprescriptions are difficult to retrieve in a retrospective study. Thus, we decided to focus only on anticancer drugs and not to collect information on all of the drugs that were prescribed to those patients.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

Patient Demographics

In total, 4684 patients with various types of cancer were included in the study from 15 participating centers. Of these, 64.4% of patients were women, and the mean age of all patients was 58.1 years (range, 18–95 years). The 5 most frequently occurring types of cancer in the study population were breast (1898 patients; 41%), colorectal (573 patients; 12.2%), lung (445 patients; 9.5%), ovarian (270 patients; 5.8%), and prostate (222 patients; 4.7%).

Renal Insufficiency

Table 1 lists the demographic characteristics for 4684 patients studied together with the estimates of renal function obtained using the Cockcroft-Gault and aMDRD formulae. Among the whole population of patients, 339 patients (7.2%) had SCR levels >110 μmol/L. However, a large majority of patients had decreased GFR or CrCl: 57.4% and 52.9% of patients had abnormal CrCl (<90 mL per minute) when calculated according to the Cockcroft-Gault formula and the aMDRD formula, respectively (Table 1). This high prevalence of RI also was observed in 3903 patients who had normal SCR levels: 60.3% and 54.7% of patients had abnormal CrCl (<90 mL per minute) calculated according to the Cockcroft-Gault formula and the aMDRD formula, respectively (Table 2).

Table 1. Creatinine Clearance of the 4684 Renal Insufficiency and Anticancer Medications (IRMA) Study Patients According to Cockcroft-Gaultand Abbreviated Modification of Diet in Renal Disease Formulae*
VariableAll patientsCrCl
Cockcroft-Gault formulaaMDRD formula
<30mL/min30–59 mL/min60–89 mL/min≥90 mL/min<30 mL/min30–59 mL/min60–89 mL/min>90 mL/min
  • CrCl indicates creatinine clearance; aMDRD, abbreviated Modification of Diet in Renal Disease; M:F, males:females; SCR, serum creatinine.

  • *

    Values for age, weight, SCR, and CrCl are reported as the mean ± standard deviation.

No. of patients468461864176015134351819151766
%1001.318.537.632.30.9211.140.937.7
Sex ratio (M:F)0.55 (1667:3017)0.9 (29:32)0.46 (272:592)0.56 (633:1127)0.62 (579:934)1.26 (24:19)0.54 (182:336)0.51 (649:1266)0.61 (672:1094)
Age, y58.1 ± 13.171.4 ± 11.767.2 ± 10.359.7 ± 11.150.5 ± 12.467.4 ± 12.365.4 ± 11.260 ± 11.853.9 ± 13.5
Weight, kg65.8 ± 13.959 ± 15.558.4 ± 1163.9 ± 11.872.7 ± 14.667.7 ± 15.367.4 ± 13.766.9 ± 14.164.3 ± 13.6
SCR, μmol/L78.3 ± 35.4248.3 ± 157.796.8 ± 27.176. ± 1663.4 ± 14.1312.2 ± 151114.1 ± 22.680.3 ± 1259.9 ± 10.8
CrCl, mL/min83.3 ± 30.722.1 ± 6.849.2 ± 7.874.6 ± 8.5115.4 ± 23.619.7 ± 7.450.7 ± 7.376.1 ± 8.2113.6 ± 31.5
Table 2. Creatinine Clearance of the 3903 Renal Insufficiency and Anticancer Medications (IRMA) Study Patients With Normal Serum Creatinine Levels According to Cockcroft-Gault and Abbreviated Modification of Diet in Renal Disease Formulae
Variable*All patients with normal SCRCrCl
Cockcroft-Gault formulaaMDRD formula
<30mL/min30–59 mL/min60–89 mL/min≥90 mL/min<30 mL/min30–59 mL/min60–89 mL/min>90 mL/min
  • CrCl indicates creatinine clearance; aMDRD, abbreviated Modification of Diet in Renal Disease; SCR, serum creatinine; M:F, males:females.

  • *

    Values for age, weight, SCR, and CrCl are reported as the mean ± standard deviation.

No. of patients3903864117041510025518821766
%1000.216.443.738.706.548.237.7
Sex ratio (M:F)0.49 (1289:2614)(8:0)0.23 (120:521)0.52 (582:1122)0.62 (576:934)0.004 (1:254)0.49 (616:1266)0.61 (672:1094)
Age, y57.6 ± 13.184.6 ± 8.867.6 ± 10.559.9 ± 11.150.6 ± 12.365.6 ± 11.660 ± 11.853.9 ± 13.5
Weight, kg65.5 ± 13.945.1 ± 454.9 ± 8.963.2 ± 11.272.7 ± 14.664.5 ± 1466.8 ± 14.164.3 ± 13.6
SCR, μmol/L71.8 ± 15.795.4 ± 8.384.1 ± 13.274.5 ± 13.963.3 ± 13.895.7 ± 6.279.7 ± 11.259.9 ± 10.8
CrCl, mL//in86.6 ± 29.427.2 ± 3.450.7 ± 7.174.8 ± 8.5115.4 ± 23.654.4 ± 3.876.4 ± 8113.6 ± 31.5

In patients with the 5 most frequently occurring types of cancer, elevated SCR levels ranged from 1.7% of patients with breast cancer to 14.9% of patients with prostate cancer (Fig. 1). When renal function was estimated using the Cockcroft-Gault and aMDRD formulae, the proportion of patients with RI was markedly higher. For example, among patients with breast cancer, 51.8% and 50.8% of patients had abnormal renal function (<90 mL per minute) according to the Cockcroft-Gault formula and the aMDRD formula, respectively (Fig. 1).

thumbnail image

Figure 1. %age of patients with renal insufficiency determined by serum creatinine levels (>110 μmol/L) and creatinine clearance (<90 mL per minute) calculated by Cockcroft-Gault and abbreviated Modification of Diet in Renal Disease (aMDRD) formulae for the whole population and by cancer type (the 5 most frequently occurring types of cancer in the study population).

Download figure to PowerPoint

The prevalence of RI across the different cancer types varied from 51.8% of patients with breast cancer to 75.2% of patients with ovarian cancer when the Cockcroft-Gault formula was used to calculate renal function (Fig. 1). When the aMDRD formula was used, the prevalence of RI varied between cancer types, from 50.8% of patients with breast cancer to 56.0% of patients with lung cancer (Fig. 1).

In 15.4% of elderly patients aged >75 years, SCR was elevated. However, when renal function was estimated appropriately with the aMDRD formula,15, 16 74.1% of these patients had RI according to the official definition, ie, GFR <90 mL per minute/1.73 m2. Among these patients, 46.9%, 22.9%, and 4.3% had stage 2, 3, and 4 or 5 chronic kidney disease, respectively.

Anemia was observed in approximately half of the total population: 49.2% of the 3017 women had serum hemoglobin levels <12 g/dL, and 63.3% of the 1667 men had serum hemoglobin levels <13 g/dL. Within the whole population of IRMA patients, 25.9% had serum hemoglobin levels <11 g/dL.

Anticancer Drugs

The study population of 4684 patients had 7181 prescriptions for anticancer drugs, resulting in a mean number of 1.5 drugs per patient. In all, 18.4% of patients were not receiving any anticancer treatment.

The prescriptions included 75 different drugs (Table 3). Of the 7181 prescriptions, 53.4% were for drugs for which a dosage adjustment was necessary or for which there were no available data concerning administration in patients with RI (Fig. 2A), and 53.3% of the drugs were nephrotoxic (Fig. 3A). Of the patients who received an anticancer drug, 79.9% received at least 1 drug that required a dosage adjustment or for which there were no data for use in patients with RI (Fig. 2B), and 80.1% received at least 1 drug that was nephrotoxic (Fig. 3B).

thumbnail image

Figure 2. Anticancer therapies requiring dosage adjustment as a percentage of prescriptions (A) and as a percentage of treated patients (B).

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thumbnail image

Figure 3. Anticancer therapies considered nephrotoxic as a percentage of prescriptions (A) and as a percentage of treated patients (B).

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Table 3. Anticancer Drugs Most Often Prescribed to Patients in the Study*
INNNo. of prescriptionsPercentage of all prescriptionsNeed for dosage adjustmentPotential nephrotoxicity
  • INN indicates International Nonproprietary Name; 5-FU, 5-fluorouracil.

  • *

    Anticancer drugs that were prescribed in <1% of patients in the Renal Insufficiency and Anticancer Medications (IRMA) study (decreasing number of prescriptions): ifosfamide, vincristine, cetuximab, rituximab, bleomycin, vinblastine, dacarbazine, mitoxantrone, mitomycin, topotecan, vindesine, fotemustine, pamidronate, cytarabine, pirarubicin, tamoxifen, procarbazin, letrozole, raltitrexed, anastrozole, thiotepa, actinomycin, exemestane, pemetrexed, goserelin, ecetinascidine, interferon, aldesleukin, temozolomide, bevacizumab, bicalutamide, imatinib, leuprorelin, diethylstilbestrol, estramustin, fludarabine, irofulven, gefitinib, tegafur uracile, nilutamide, lomustine, triptoreline, melphalan, megestrol, vinflunine, cyproterone, aplidine, ixabepilone, busulfan, bortezomib, clodronate, edotecarine, infliximab, indisulam, pixantrone, and streptozocin.

5-FU118216.46NoNo
Cyclophosphamide7019.76YesNo
Docetaxel6018.37YesNo
Epirubicin5567.74NoYes
Gemcitabine4285.96NoYes
Vinorelbine3905.43YesNo
Carboplatin3785.26YesYes
Doxorubicin3404.73NoYes
Paclitaxel3284.57NoYes
Cisplatin3134.36YesYes
Oxaliplatin3024.21NoYes
Irinotecan2583.59No data availableYes
Trastuzumab2563.56No data availableYes
Zoledronate1532.13YesYes
Etoposide1311.82YesNo
Capecitabine921.28YesNo
Methotrexate811.13YesYes
Total90.36   

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

In this study, we observed that RI is highly prevalent in patients with cancer. However, it is clear that the frequency of RI routinely is underestimated in clinical practice, because physicians most often base their diagnosis on SCR measurements. It is crucial to emphasize that SCR is not appropriate for evaluating renal function if it is not interpreted together with the sex, age, and weight of the patient. These parameters represent the muscle mass of the patient and, thus, the creatinine production rate. Therefore, it is crucially important to evaluate renal function with the appropriate tools in all patients, including patients with cancer, by estimating CrCl or GFR using either the Cockcroft-Gault formula or the aMDRD formula. This includes patients who have normal SCR levels; because, even in those patients who had SCR levels within the normal range, the frequency of RI, as estimated with 1 of the 2 recommended formulae, was 60.3% (Cockcroft-Gault formula) and 54.7% (aMDRD formula) of the patients with stage ≥2 RI.

The use of those formulae is crucial and should be systematic. Other methods to asses the GFR ie, renal function, also may be used. Such methods include a 24-hour urine collection to measure CrCl or a measure of the actual GFR using a specific marker of renal filtration, such as inulin, iothalamate, or 51 chrome-ethylenediaminetetraacetate (51 Cr-EDTA), for instance. However, such methods necessitate a trained staff and time, and they are not cost effective for the systematic evaluation of renal function. They must be used only in some specific patients, and those who may benefit from such a determination of renal function should be carefully identified together with nephrologists, according to the patient's profile and their estimated renal function according to the Cockcroft-Gault or aMDRD formulae.

To date, we have identified no data that allow recommending the use of 1 formula over the other, either in oncology patients or in the general population. Most often, differences between the 2 formulae in terms of renal function are weak. When the Cockcroft-Gault and the aMDRD estimates differ, it may be useful to consider a measure of the actual GFR after discussions with a nephrologist.

The frequency of RI in the general population with cancer probably would be even greater than that reported in the current study, because patients with multiple myeloma were excluded. In the IRMA study, investigators decided not to include patients with hematologic malignancies, because the high frequency of abnormal renal function in those patients already was known. Indeed, it is known that RI occurs in approximately 50% of patients with multiple myeloma at some point during the course of their disease.17 Because data were lacking for patients with solid tumors, the IRMA Scientific Committee decided to focus on this group of patients.

In the IRMA study, the prevalence of RI was higher than that reported in our pilot study5 and in the study by Dogan et al.6 The reason for this difference may be that, in our pilot study, we used a different definition of RI. For the IRMA study, we used the official recommendations and guidelines from the K/DOQI and the K/DIGO for the definition and stratification of RI/kidney disease.9 Dogan et al. also used this stratification and definition in their study. The difference between the prevalence of RI we observed in IRMA study and that reported by Dogan et al. may have resulted from differences in patient populations. In the IRMA study, we included 4684 cancer patients, compared with 1217 patients in the study by Dogan et al. Furthermore, there was a high proportion of patients with breast cancer in our study, whereas Dogan et al. had a high number of patients with gastrointestinal tumors; and the patients studied by Dogan et al. were younger than the patients studied in IRMA (mean age, 52 years and 58 years, respectively).

In the IRMA study, most patients had a stage 2 RI according to the K/DOQI definition. This means that their CrCl or GFR, estimated with the Cockcroft-Gault formula or the aMDRD formula, were within 60 and 90 mL per minute, respectively (37.6% according to the Cockcroft-Gault formula; 40.9% according to the aMDRD formula). For such a decrease in renal function, drug dosage adjustments rarely are necessary apart from some well-known examples in oncology, such as carboplatin, which necessitates adjustment of its dosage to renal function whatever the value of CrCl (formulae published by Calvert et al.18 and Chatelut et al.19). For most drugs, however, the pharmacokinetic changes induced by RI for this degree of impairment are not significant to require a modification of the dosage.

In patients with stage 2 RI, potential drug nephrotoxicity is the main issue. Many studies have demonstrated that pre-existing abnormal renal function is a risk factor for drug-induced nephrotoxicity.20 Consequently, in those patients who have mildly decreased renal function, anticancer drugs and antineoplastic or supportive care should be selected cautiously to administer drugs that either are not nephrotoxic or are less nephrotoxic.20

When renal function is <60 mL per minute, the risk for nephrotoxicity is even higher; moreover, the clinical consequences are more severe, because any further deterioration of renal function may precipitate end-stage renal disease. In those patients, in addition to nephrotoxicity, the question of drug dosage adjustment is crucial to avoid an overdose from the accumulation of the drug from reduced excretion and related toxicities, such as neurologic, hematologic, skeletal, cardiologic, and hepatologic toxicities. Indeed, when renal function declines and is below 60 mL per minute, pharmacokinetic changes necessitate modification of the drug dosage to ensure efficacy and safety.

In elderly patients, Verhave et al. have demonstrated that renal function should be estimated with the aMDRD formula. Indeed, in elderly cancer patients in the IRMA study, the prevalence of RI was high. Almost 75% of patients whose age was >75 years had RI, and a large number of these patients (27.2%) had stage 3, 4, and 5 RI.

Almost 80% of cancer patients received at least 1 drug that required dosage adjustment in patients with RI or for which there were no data available regarding their use in patients with RI (in either the literature or the SmPC). In patients who are receiving drugs that require dosage adjustment, CrCl should be calculated (with the Cockcroft-Gault or aMDRD formula) to prescribe drugs at their adjusted dosage in accordance with their renal function. When information is not available on dosage adjustments in patients with RI, the prescription of these drugs should be approved by a pharmacologist or nephrologist together with the oncologist in charge of the patient. When an alternative treatment exists for which recommendations are available, preferably, it should be used. In the IRMA study patients, 10.26%, 10.46%, and 10.30% of anticancer drug prescriptions in patients who had a CrCl from 90 to 60 mL per minute, from 59 to 30 mL per minute, and from 29 to 15 mL per minute, respectively, were prescriptions of drugs for which no data were available in the literature for dosage adjustment in RI. In patients who had a CrCl <15 mL per minute, this proportion was 71.43% because of the low number of prescriptions (7 prescriptions) (Table 4).

Table 4. Percentage of Anticancer Drugs Requiring Dosage Adjustment in Renal Insufficiency or With Potential Nephrotoxicity Prescribed to the Renal Insufficiency and Anticancer Medications (IRMA) Study Patients According to Cockcroft-Gault Creatinine Clearance
VariableC-G CrCl
C-G CrCl, mL/min90–60 mL/min59–30 mL/min29–15 mL/min<15 mL/min
  • C-G CrCl indicates Cockcroft-Gault creatinine clearance; RI, renal insufficiency; INN, International Nonproprietary Name.

  • *

    For dosage adjustment, yes indicates the percentage of prescriptions of drugs for which dosage adjustment is mandatory in RI; ND, the percentage of prescriptions of drugs for which there are no data on whether or not it would be necessary to adjust dosage in RI; no, the percentage of prescriptions of drugs for which no dosage adjustment is mandatory in RI.

  • For nephrotoxicity, yes indicates the percentage of prescriptions for potentially nephrotoxic drugs; no, the percentage of prescriptions for nonnephrotoxic drugs.

Stage of RI2345
No. of patients17608645110
No of INN drugs6226164
No. of prescriptions26961121397
Dosage adjustment, %*
 Yes41.7544.2738.628.57
 ND10.2610.4610.371.43
 No47.9945.2751.10
Nephrotoxicity, %
 Yes53.660.267100
 No46.439.8330

The use of potentially nephrotoxic therapies in patients who are at high risk for drug renal toxicity because of preexisting renal impairment should be avoided if possible, and alternative treatments should be considered. However, in the IRMA study patients who had at least stage 2 RI, the frequency of nephrotoxic drug prescriptions still was high. In patients who had a CrCl from 90 to 60 mL per minute, from 59 to 30 mL per minute, and from 29 to 15 mL per minute, 53.6%, 60.2%, and 67% of anticancer drug prescriptions, respectively, were potentially nephrotoxic compounds. In patients who had a CrCl <15 mL per minute, the low number of prescriptions meant that the data are difficult to interpret (Table 4).

In cancer therapy, the choice of the anticancer drug in each patient obeys multiple rules and criteria, for example, indications and protocols. It may not be always possible to avoid using potentially nephrotoxic drugs. However, it remains very important to be aware of the renal function of patients who receive potentially nephrotoxic drugs. If a nephrotoxic prescription is mandatory, and there is no other, better tolerated alternative, means of prevention of renal toxicity should be used together with the elimination of potential risk factors for renal toxicity (Table 5). Preventative methods include appropriate hydration and monitoring of both diuresis and renal function (CrCl) together with appropriate dosage adjustment in patients who are receiving cisplatin. Furthermore, in those patients who require nephrotoxic antineoplastic chemotherapy, cautious selection and analysis of associated drugs should be performed. For example, nonsteroidal antiinflammatory drugs, when possible, should be avoided because they may potentiate the renal toxicity of the chemotherapy. Similarly, vomiting should be monitored strictly, treated, and most often prevented to avoid dehydration.

Table 5. Risk Factors for Anticancer Drug-induced Renal Toxicity: Example of Cisplatin
Repeated administrations and frequent courses
✓Cumulative dose >450 mg/m2
✓Pre-existing renal disease/abnormal renal function
✓Dehydration
✓Heart failure, adema, ascites, etc
✓Anemia
✓Coadministration of other nephrotoxic agents
✓Dosage not adjusted to the level of renal function

Regarding the treatment of bone metastases, when a bisphosphonate is to be prescribed, the same selection rules should be applied according to renal tolerance and dosage adjustment. Similarly, it has been demonstrated that anemia is a risk factor for contrast-induced nephropathy.21 Because contrast media and platins, for instance, share similar mechanisms for renal toxicity, patients with anemia also may be at risk for chemotherapy-induced renal toxicity. In our study, almost 50% of patients had a low hemoglobin level and, thus, may have been at risk for drug-induced renal toxicity.

In conclusion, from 50% to 60% of the 4684 cancer patients in the IRMA study had abnormal renal function, whereas SCR levels were normal in most patients. Therefore, in clinical practice, patients with cancer should have their renal function evaluated systematically with the appropriate methods. Renal function should be evaluated by calculation with either the Cockcroft-Gault formula or the aMDRD formula. Such a high prevalence of abnormal renal function has crucial consequences on anticancer drugs handling.

Once RI has been diagnosed, anticancer drugs should be selected cautiously in those patients who are at risk for drug-induced nephrotoxicity and who commonly necessitate adjustment of their dosage. When possible, nonnephrotoxic drugs should be used instead of potentially toxic drugs. Those drugs for which the recommendations of use are known clearly should be used as a priority compared with those drugs for which data are lacking.

The IRMA study is the first large cohort study that allows a clearer estimation of the frequency of abnormal renal function in cancer patients. Furthermore, results from the study indicate that, in addition to the high frequency of RI, the anticancer drugs that are prescribed to those patients interact with the kidneys in terms of excretion or potential toxicity, thus requiring dosage adjustments in patients with RI and specific, close monitoring.

Acknowledgements

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

We are indebted to the physicians who took time from their busy work schedules to participate in the Renal Insufficiency and Anticancer Medications (IRMA) Study Group and to Julien Bruschini from Roche France, thanks to whom Information and Counselling on Renal Adaptation (ICAR) services are now offered to French oncologists through an unrestricted educational grant. We also thank Gardiner-Caldwell U.S. for assistance in preparing this article.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES
  • 1
    Matas AJ, Simmons RL, Kjellstrand CM, Buselmeier TJ, Najarian JS. Increased incidence of malignancy during chronic renal failure. Lancet. 1975; 1: 883886.
  • 2
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