Drug management of prostate cancer: prevalence and consequences of renal insufficiency.

Abstract

The Renal Insufficiency and Anticancer Medications (IRMA) study reported a renal insufficiency (RI) prevalence of 50%-60% in a population of almost 5000 patients with solid tumors, 80% of whom were being treated with anticancer drugs that either necessitated dosage adjustment or were potentially nephrotoxic drugs. A national multicenter study from 15 cancer centers in France analyzed IRMA data on patients with prostate cancer.
Data on patients with prostate cancer from the IRMA study were analyzed. Renal function was calculated using Cockcroft-Gault and abbreviated Modification of Diet in Renal Disease (aMDRD) formulas to estimate the prevalence of RI. Anticancer drugs' potential renal toxicity and need for dosage adjustment were detailed.
Of the 222 IRMA patients with prostate cancer, 14.9% had a serum creatinine (SCr) level of > 110 micromol/L. When using Cockcroft-Gault and aMDRD formulas, 62.6% and 55.9%, respectively, of the patients had RI. Of the 228 anticancer drug prescriptions, 82.9% required dose adjustments for RI or were drugs with no available data on their administration in patients with RI. Of the patients treated, 86.9% received >or= 1 such drug, but only 29.1% received nephrotoxic drugs.
The prevalence of RI in patients with prostate cancer was very high in spite of a normal SCr level in most cases. Some anticancer drugs, particularly some bisphosphonates and platinum salts, might be nephrotoxic and/or need dosage adjustment. However, other important drugs in prostate cancer, such as docetaxel, neither require dose reduction nor present with potential nephrotoxicity. Both issues were significantly more important in the patients with bone metastases compared with those with nonmetastatic disease.

Full text

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Drug Management of Prostate Cancer:
Prevalence and Consequences of
Renal Insufficiency
Vincent Launay-Vacher,1 Jorge
Ayllon,2 Nicolas Janus,1 Jean-
Philippe Spano,3 Isabelle Ray-
Coquard,4 Joseph Gligorov,5
Xavier Pourrat,6 Jean-François
Morere,7 Philippe Beuzeboc,8
Gilbert Deray,1 Stéphane
Oudard,2 Renal Insufficiency
and Anticancer Medications
(IRMA) Study Group
1Nephrology, Hôpital Pitié-Salpêtrière, Paris, France
2Medical Oncology, Hôpital Européen Georges Pompidou,
Paris, France
3Medical Oncology, Hôpital Pitié-Salpêtrière, Paris, France
4Medical Oncology, Léon Bérard Cancer Center, Lyon, France
5Medical Oncology, Hôpital Tenon, Paris, France
6Clinical Pharmacy, Hôpital Troussau, Tours, France
7Medical Oncology, Hôpital Avicenne, Bobigny, France
8Medical Oncology, Institut Curie, Paris, France
Clinical Genitourinary Cancer,
Vol. 7, No. 3, E83-E89, 2009
Keywords: Anemia, Cockcroft-Gault, Dosage
adjustment, IRMA, Nephrotoxicity
DOI: 10.3816/CGC.2009.n.029
Submitted: Jan 6, 2009; Revised: Mar 17, 2009;
Accepted: Apr 8, 2009
Address for correspondence:
Vincent Launay-Vacher, PharmD, Department of
Nephrology Pr. Deray, Hôpital Pitié-Salpêtrière,
47-83 Boulevard de l’Hôpital, 75013 Paris, France
Fax: 33-0-1-42-17-72-12;
E-mail: vincent.launay-vacher@psl.aphp.fr
Introduction
Renal insufficiency (RI) is known to be a common pathology in the general
population,1 and since the Renal Insufficiency and Anticancer Medications
(IRMA) study,2 it has also been demonstrated that it is highly frequent in pa-
tients with solid tumors. However, a reduction in renal function < 90 mL/minute
is often considered nonsignificant; in the oncology setting, such a reduction in
renal function should be considered as an indicator for a potential developing
underlying kidney disease not related to cancer. Further renal investigations, for
instance urinalysis, would be warranted in order to search for organic kidney
damages. Such a reduction also means that the kidneys might have reached their
maximum filtration rate, with no more ability to hyperfiltrate and compensate
for any damage due to drug toxicity, leaving patients with such reductions at
risk for renal impairment following nephrotoxic drug administration. This
should be considered a risk factor for developing more severe RI, or acute renal
failure, especially in patients aged around 60 years.
For patients who are diagnosed with RI and whose creatinine clearance
(CrCl) is < 60, the risk for renal failure is even more important, and the dos-
Background: The Renal Insufficiency and Anticancer Medications
(IRMA) study reported a renal insufficiency (RI) prevalence of 50%-60%
in a population of almost 5000 patients with solid tumors, 80% of whom
were being treated with anticancer drugs that either necessitated dos-
age adjustment or were potentially nephrotoxic drugs. A national multi-
center study from 15 cancer centers in France analyzed IRMA data on
patients with prostate cancer. Patients and Methods: Data on patients
with prostate cancer from the IRMA study were analyzed. Renal function
was calculated using Cockcroft-Gault and abbreviated Modification of
Diet in Renal Disease (aMDRD) formulas to estimate the prevalence of
RI. Anticancer drugs’ potential renal toxicity and need for dosage adjust-
ment were detailed. Results: Of the 222 IRMA patients with prostate
cancer, 14.9% had a serum creatinine (SCr) level of > 110 µmol/L.
When using Cockcroft-Gault and aMDRD formulas, 62.6% and 55.9%,
respectively, of the patients had RI. Of the 228 anticancer drug prescrip-
tions, 82.9% required dose adjustments for RI or were drugs with no
available data on their administration in patients with RI. Of the patients
treated, 86.9% received ≥ 1 such drug, but only 29.1% received neph-
rotoxic drugs. Conclusion: The prevalence of RI in patients with prostate
cancer was very high in spite of a normal SCr level in most cases. Some
anticancer drugs, particularly some bisphosphonates and platinum salts,
might be nephrotoxic and/or need dosage adjustment. However, other
important drugs in prostate cancer, such as docetaxel, neither require
dose reduction nor present with potential nephrotoxicity. Both issues
were significantly more important in the patients with bone metastases
compared with those with nonmetastatic disease.
Abstract
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Clinical Genitourinary Cancer October 2009 • E83

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Prostate Cancer and Renal Insufficiency
E84 • Clinical Genitourinary Cancer October 2009
age of a number of anticancer drugs might need to be adjusted to
the level of RI in order not to overdose the patient. Because some
anticancer drugs used in prostate cancer are excreted predominantly
in the urine as unchanged drug or active metabolites, any reduc-
tion in renal clearance results in accumulation of potentially toxic
species and overdosage. The dosage of chemotherapeutic agents
used in patients with RI will, therefore, require dosage reduction to
avoid severe toxicities. Furthermore, using potentially nephrotoxic
anticancer drugs will require specific monitoring and specific pre-
vention methods, when available, in order to help reduce the risk
of renal toxicity, especially in patients with baseline abnormal renal
function before anticancer therapy is started.
In addition to cancer therapy, the growing use of intravenous
bisphosphonates in patients with prostate cancer emphasizes the
need for regular monitoring of renal function, with particular atten-
tion to patients with preexisting impaired renal function.
In patients with prostate cancer and bone metastases (BM), there
is a paucity of data on the optimal use of bisphosphonates, mainly re-
garding initiation and treatment duration. Benefit with zoledronate
and ibandronate for a treatment duration of up to 2 years has been
demonstrated.3,4 Renal safety must be considered because, over the
past few years, case reports and randomized trials5 have raised cases
of renal toxicity with intravenous bisphosphonates, such as zole-
dronic acid–associated renal impairment leading to renal failure.6
Monitoring must include an appropriate evaluation of CrCl in
patients receiving intravenous bisphosphonates because serum cre-
atinine (SCr) values can be misleading.
Following are results from a subgroup analysis of the 222 patients
with prostate cancer in the IRMA population.
Patients and Methods
The IRMA study included a total of 4684 patients being treated
for solid tumors in an oncology department, either in hospital or
as outpatients. The study consisted of a retrospective patient data
collection on 1 of 2 specific 15-day time periods between either
February 1 and the February 15, 2004 or October 1 and October
15, 2004. These time periods were selected to avoid summer vaca-
tions and to be representative of the whole year, with a period in
winter/spring and another in fall/winter. Patients were included
regardless of disease pathology and treatment (antineoplastic drugs
used/to be used, pretreated or not). Patients were excluded if they
were aged < 18 years, had a diagnosis of myeloma, or presented with
end-stage renal disease requiring renal replacement therapy (either
hemodialysis or peritoneal dialysis) because the aim of the IRMA
study was to determine the prevalence of potentially undiagnosed
RI (dialysis patients present with the disease).
The following data were collected for each patient: sex, age,
weight, SCr, blood urea nitrogen, hemoglobinemia, type of tumor,
metastasis, and anticancer drugs prescribed. Patients who were
known to present with acute renal failure were excluded in order
to determine the prevalence of potentially chronic abnormal renal
function. Estimations of renal function were made by calculations
from SCr using the Cockcroft-Gault (CG)7 and the abbreviated
Modification of Diet in Renal Disease (aMDRD)8 formulas. The
CG formula is CrCl (mL/minute) = k × [(140–age) × weight
(kg)]/SCr (µmol/L), where k = 1.23 for a man and 1.04 for a
woman. The aMDRD formula is glomerular filtration rate (GFR;
mL/minute/1.73 m2) = k × 186 × [SCr (mg/dL)]–1.154 × [age]–0.203,
where k = 1 for a man and 0.742 for a woman.
Renal function, calculated using either formula, was staged in
accordance with the international clinical practice guidelines from
the Kidney Disease Outcomes Quality and the Kidney Disease Im-
proving Global Outcomes KDIGO groups.9,10 Stage 1 was defined
as GFR ≥ 90 mL/minute, stage 2 as GFR 60-89 mL/minute, stage 3
as GFR 30-59 mL/minute, stage 4 as GFR 15-29 mL/minute, and
stage 5 as GFR < 15 mL/minute.
With regard to anticancer therapies prescribed to study patients,
those requiring dosage adjustment were identified in accordance
with their pharmacokinetics and available recommendations from
both their individual Summary of Product Characteristics (SmPC)
and 2 specific reference books on drug dosage adjustment in pa-
tients with RI (Drug Prescribing in Renal Failure: Dosing Guidelines
for Adults and GPR Anticancéreux: Guide de Prescription des Médica-
ments Chez le Patient Insuffisant Rénal).11,12 Anticancer therapies
were then 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 using PubMed was performed to identify any potential renal
side effects of the therapies. If at least some cases of nephrotoxicity
were retrieved, the therapy was classified as “Yes,” meaning poten-
tially nephrotoxic. Therapies were labeled “No” when no cases had
been found or there were no suggestions of potential renal toxicity.
As a result, some drugs with different risks for renal toxicity might
be similarly classified as “Yes.”
Results
Demographics
A total of 222 patients with prostate cancer were included in the
prostate cancer subgroup analysis. Mean age was 67.7 ± 8.3 years,
mean weight was 75 ± 11.6 kg, and 79.3% of the patients had nor-
mal a SCr level (< 110 µmol/L). The incidence of BM was 75.3%.
Renal Insufficiency
Table 1 illustrates the percentages of patients among the 5 stages
of RI, and Figure 1 presents the number of patients in each stage
according to the formula, either CG or aMDRD, used to estimate
renal function.
For 13 patients (5.9%), no SCr could be retrieved in the medical
file, and among the whole population of patients with prostate can-
cer, 33 (14.9%) had a SCr level ≥ 110 µmol/L. In spite of this low
proportion of patients with elevated SCr, the majority of patients had
a decreased CrCl or estimated GFR (eGFR) level; 62.6% and 55.9%
of the patients had abnormal renal function (< 90 mL/minute) and
18.0% and 14.4% actual kidney disease (< 60 mL/min) when cal-
culated using the CG and aMDRD formulas, respectively (Table 1).
This high prevalence of RI was also observed in the 176 patients
(79.3%) whose SCr levels were normal (< 110 µmol/L), with 60.2%
and 51.7% of patients having abnormal renal function when calcu-
lated using the CG and aMDRD formulas, respectively.
The prevalence of RI in IRMA patients with prostate cancer was
also studied in the patients with BM compared with those without

Page 3

BM. The level of SCr was elevated (≥ 110 µmol/L) in 17.6% of
the patients with BM and available SCr value and 10.0% of those
without BM (P > .05; Table 2). The patients with BM and those
without BM did not significantly differ in mean age, weight, and
SCr. Although mean CG values were the same, eGFR estimated
with the aMDRD formula was significantly higher in the BM
group than in the no BM group (88.5 mL/minute/1.73 m2 vs.
80.9 mL/minute/1.73 m2; P = .0452). Mean hemoglobin level also
was different between the 2 groups, with a lower mean value in the
patients with BM compared to those without BM (Table 2; 11.1 vs.
12.3 g/dL; P = .0001).
However, when calculating the prevalence of RI in the 2 groups
of patients, some significant differences appeared with both formu-
las (Table 3). The prevalence of renal dysfunction was as follows:
62.9% of the patients with prostate cancer and BM had a CG
CrCl < 90 mL/minute compared with 81.3% of those without BM
(P = .0176), and 55.4% of the patients with prostate cancer and BM
had an aMDRD eGFR < 90 mL/minute/1.73 m2 vs. 72.0% in those
without BM (P = .0365). Thus, there was a statistically significant
difference in the prevalence of RI in the patients with BM compared
with those without BM, with a higher proportion of the latter pre-
senting with RI.
Anemia according to the World Health Organization defini-
tion (< 13 g/dL in men) was observed in 77.5% of the IRMA
patients with prostate cancer. Further analysis revealed that 10.8%
and 29.7% of the patients had a hemoglobin level < 9 g/dL and
9-11 g/dL, respectively. For 4.5% of the patients, no hemoglobin
value was available in the medical file. Comparing the patients with
data on BM status and those for whom a hemoglobin value was
available, it appeared that the patients with BM had a statistically
significantly (P = .0353) higher incidence of hemoglobin levels
of 9-11 g/dL (34.2% vs. 22.2%) and < 9 g/dL (13.3% vs. 5.6%)
compared with those without BM (Table 4).
Anticancer Drugs
Of the total study population of 222 patients with prostate can-
cer, 78.8% were receiving anticancer drugs during the time period
studied, resulting in 175 treated patients and 228 total anticancer
drug prescriptions (1.3 drugs/patient).
The prescriptions comprised 26 different drugs, of which 34.6%
were drugs necessitating dosage adjustment in RI and 38.5% were
drugs for which no data were available in the literature on whether
dosage adjustment would be necessary in case of RI (Table 5). Of
the 228 prescriptions, 82.9% were for drugs for which a dosage ad-
justment was necessary (74.1%) or for which there were no available
data concerning administration in patients with RI (8.8). Finally,
78.9% of the patients were receiving ≥ 1 drug that necessitates dos-
age adjustment in RI and 8.0% ≥ 1 drug for which no data were
available, resulting in a total 86.9% of IRMA patients with prostate
cancer with ≥ 1 drug for which caution is mandatory in RI (either
dosage adjustment required or no data available). Regarding neph-
rotoxicity, 42.3% of the drugs were potentially toxic to the kidneys,
StageStage
Number of PatientsNumber of Patients
Renal Function by Cockcroft-Gault and aMDRD in
222 IRMA Patients With Prostate Cancer
Table 1
1 (? 90)
2 (60-89)
3 (30-59)
4 (15-29)
5 (< 15)
No Data
Cockcroft-Gault CrCl,
mL/minute (%)mL/minute (%)
Cockcroft-Gault CrCl,
68 (30.6)
99 (44.6)
33 (14.9)
7 (3.1)
0
15 (6.8)
aMDRD eGFR,
mL/minute/1.73 m2 (%)mL/minute/1.73 m2 (%)
aMDRD eGFR,
85 (38.3)
92 (41.4)
26 (11.7)
5 (2.2)
1 (0.5)
13 (5.9)
Abbreviations: aMDRD = abbreviated Modification of Diet in Renal Disease;
CrCl = creatinine clearance; eGFR = estimated glomerular filtration rate;
IRMA = Renal Insufficiency and Anticancer Medications
Renal Insufficiency by Cockcroft-Gault and aMDRD
in Patients With Prostate Cancer
Figure 1
Number of Patients
0
Stage of Renal Insufficiency
(Glomerular Filtration Rate, mL/minute)
20
40
60
80
100
120
1
(? 90)
2
(60-89)
3
(30-59)
4
(15-29)
5
(< 15)
No Data
Cockcroft-Gault
aMDRD
Abbreviation: aMDRD = abbreviated Modification of Diet in Renal Disease
CharacteristicCharacteristic
Patients With
Bone Metastases
(n = 167)(n = 167)
Mean Mean
Patients With
Bone Metastases
Patients Without
Bone Metastases
(n = 55)(n = 55)
MeanMean
Patients Without
Bone Metastases
IRMA Study: Characteristics of Patients With Prostate
Cancer With or Without Bone Metastases
Table 2
Age, Years
Weight, kg
SCr, µmol/L
Cockcroft-Gault,
mL/minute
aMDRD, mL/
minute/1.73 m2
Hemoglobin, g/dL
67.7
74.5
92.4
82.0
88.5
11.1
SD SD
8.3
11.7
50.5
28.2
31.4
1.9
67.8
76.5
94.5
75.7
80.9a
12.3b
SD SD
8.6
11.2
42.6
18.1
20.1
2.2
aP = .0452 compared with those with bone metastases.
bP = .0001 compared with those with bone metastases.
Abbreviations: aMDRD = abbreviated Modification of Diet in Renal Disease;
IRMA = Renal Insufficiency and Anticancer Medications; SCr = serum creatinine
Clinical Genitourinary Cancer October 2009 • E85
Vincent Launay-Vacher et al

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E86 • Clinical Genitourinary Cancer October 2009
Prostate Cancer and Renal Insufficiency
resulting in 25.4% of the prescriptions for drugs that might be
nephrotoxic, and 29.1% of the IRMA patients with prostate cancer
were receiving ≥ 1 such drug.
Discussion
In this study, we found that RI (defined as an eGFR < 90) is
highly prevalent in patients with prostate cancer. However, the fre-
quency of RI is clearly routinely underestimated in clinical practice
because physicians most often base their diagnosis on SCr measure-
ments. It is crucial to outline that SCr is not appropriate for evaluat-
ing renal function. We observed that only 5.9% of the patients in
our analysis had no report of SCr determination in their file, mean-
ing that the monitoring of renal function was actually performed in
patients with prostate cancer in routine practice.
It is, however, of major importance that renal function is ap-
propriately evaluated not only with a SCr determination but by
estimating CrCl or GFR using either the CG or aMDRD formula,
in all patients with prostate cancer. This includes patients who have
normal SCr levels because even in those patients with so-called
normal SCr levels, abnormal renal function was still present in more
than half of the patients. However, CrCl and eGFR were rarely < 60
(CG: 5.7%; aMDRD: 0). As a result, it could be concluded that
when SCr is normal in patients with prostate cancer, patients do
not need dosage adjustment because their renal function is rarely
< 60, the level at which dosages need adjustment. Such an observa-
tion should not be made as a general rule, however. In fact, in other
subgroups of IRMA patients, such an association between normal
SCr and an eGFR > 60 has not been retrieved.2 If such a conclusion
is supported by our results, it must be emphasized that calculat-
ing renal function is not time consuming nor expensive. Most of
the time, such a calculation is automatically performed within the
computerized prescription systems, and physicians just have to con-
sider this value rather than that of SCr. There might be some dis-
crepancies between the calculated and the actual renal function in
some patients. However, such significant deviations often occur in
patients for whom calculation is not appropriate, such as those who
are obese or elderly, for whom CG cannot be used but aMDRD
can, or in those with a low body mass index, for whom neither CG
nor aMDRD allow a good estimation of renal function.
To date, there are no data allowing recommendations of 1 for-
mula over the other in oncology patients or in the general popula-
Renal FunctionRenal Function
Patients With
Bone Metastases
(n = 159)(n = 159)
Patients With
Bone Metastases
Patients Without
Bone Metastases
(n = 48)(n = 48)
Patients Without
Bone Metastases
IRMA Study: Prevalence of Renal Insufficiency
in Patients With Prostate Cancer With or Without
Bone Metastases
Table 3
Cockcroft-Gault CrCl,
mL/minute
< 90
? 90
aMDRD GFR,
mL/minute/1.73 m2
< 90
? 90
Abbreviations: aMDRD = abbreviated Modification of Diet in Renal Disease;
CrCl = creatinine clearance; GFR = glomerular filtration rate; IRMA = Renal
Insufficiency and Anticancer Medications
62.9%
37.1%
(n = 159)
55.4%
44.7%
81.3%
18.8%
(n = 50)
72.0%
28.0%
PP
ValueValue
.0176
.0365
Drug (%)Drug (%)
Number of
Prescriptions
(n = 228)(n = 228)
Number of
Prescriptions
IRMA Study: Anticancer Drugs Prescribed to
175 Patients With Prostate Cancer
Table 5
Docetaxel
Vinorelbine
Zoledronate
Mitoxantrone
Cisplatin
Carboplatin
Paclitaxel
Gemcitabine
Etoposide
Capecitabine
Bicalutamide
5-Fluorouracil
Diethylstilbestrol
Leuprorelin
Goserelin
Cyclophosphamide
Triptorelin
Estramustine
Pamidronate
Pirarubicin
Nilutamide
Cyproterone
Irinotecan
Oxaliplatin
Methotrexate
Vinblastine
Abbreviation: IRMA = Renal Insufficiency and Anticancer Medications
99 (43.42)
21 (9.21)
19 (8.33)
17 (7.46)
9 (3.95)
8 (3.51)
7 (3.07)
6 (2.63)
6 (2.63)
4 (1.75)
4 (1.75)
3 (1.32)
3 (1.32)
3 (1.32)
3 (1.32)
2 (0.88)
2 (0.88)
2 (0.88)
2 (0.88)
2 (0.88)
1 (0.44)
1 (0.44)
1 (0.44)
1 (0.44)
1 (0.44)
1 (0.44)
Need for
Dosage
AdjustmentAdjustment
Need for
Dosage
Yes
Yes
Yes
No
Yes
Yes
No
No
Yes
Yes
No
No
No data
No data
No data
Yes
No data
No data
No data
No data
No data
No data
No data
No
Yes
No
Potential
NephrotoxicityNephrotoxicity
Potential
No
No
Yes
No
Yes
Yes
Yes (isolated cases)
Yes
No
No
No
No
No
No
No
No
No
Yes
Yes
Yes (isolated cases)
No
No
Yes
Yes
Yes
No
Hemoglobin, g/dL (%)Hemoglobin, g/dL (%)
Patients With
Bone Metastases
(n = 158)(n = 158)
Patients With
Bone Metastases
Patients Without
Bone Metastases
(n = 54)(n = 54)
Patients Without
Bone Metastases
IRMA Study: Hemoglobin Values in Patients With
Prostate Cancer With or Without Bone Metastases
Table 4
? 11
9-11
< 9
aP = .0353 compared with patients with bone metastases.
Abbreviation: IRMA = Renal Insufficiency and Anticancer Medications
83 (52.53)
54 (34.18)
21 (13.29)
39 (72.22)
12 (22.22)a
3 (5.56)a

Page 5

tion. Most often, differences between the 2 formulas in terms of
renal function are weak. Some differences might be observed in the
ranging of the patients in the different stages of RI. As shown on
Figure 1, such differences between the 2 formulas were not relevant
in our patients with prostate cancer. However, when the CG and
aMDRD estimates differ in a particular patient, it might be useful
to consider a measure of the actual GFR after discussions with a
nephrologist. Such methods include a 24-hour urine collection to
measure CrCl or a measure of the actual GFR using a specific mark-
er of renal filtration, such as 51CR-EDTA. However, such methods
necessitate a trained staff as well as time and are not cost effective
for a systematic evaluation of patients’ renal function. They must be
used only in some specific cases, and the patients who might benefit
from such a determination of renal function should be closely iden-
tified together with nephrologists according to the patient’s profile
and estimated renal function with CG and aMDRD formulas.
In patients with a renal function < 90, potential drug nephrotox-
icity rather than the dosage to administer is the main issue. Some
studies have demonstrated that preexisting abnormal renal function
is a risk factor for drug-induced nephrotoxicity.13 As a result, an-
ticancer drugs, antineoplastic agents, or supportive care should be
cautiously selected in patients with mildly decreased renal function
in order to administer drugs that are not or are less nephrotoxic.
When renal function is < 60 mL/minute, the risk for nephrotox-
icity is even higher; moreover, the clinical consequences are more
severe because any further deterioration of renal function might
precipitate end-stage renal disease. In patients with such renal func-
tion, the question of drug dosage adjustment in addition to nephro-
toxicity is crucial to avoid overdose due to accumulation of the drug
from reduced excretion, and related toxicities, such as neurologic,
hematologic, skeletal, cardiologic, and hepatologic toxicities.
Nearly 90% of patients with prostate cancer in the IRMA
population received ≥ 1 drug that requires 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.
However, the vast majority of our patients had a renal function
> 60 and, thus, did not require dosage adjustment. Renal function
should be calculated by the CG or aMDRD formula in every pa-
tient in order, preferably before each course of anticancer therapy,
chemotherapy, or other type of treatment, in order to identify those
who will need a reduction in the doses of the anticancer drugs
they are prescribed. When information on dosage adjustments in
patients with RI is not available, the prescription of these drugs
should be approved by a pharmacologist or a nephrologist together
with the oncologist in charge of the patient. Preferably, alternative
treatment should be used when recommendations upon such treat-
ments are available.
The use of potentially nephrotoxic therapies in patients at high
risk for drug renal toxicity due to preexisting renal impairment
should be avoided if possible, and alternative treatments should be
considered. However, in the IRMA patients with prostate cancer,
the frequency of nephrotoxic drug prescriptions was rather low
Drug (%)Drug (%)
Number of
Prescriptions
(n = 175)(n = 175)
Number of
Prescriptions
IRMA Study: Anticancer Drugs Prescribed to 137
Patients With Prostate Cancer With Bone Metastases
Table 6
Docetaxel
Zoledronate
Vinorelbine
Mitoxantrone
Cisplatin
Paclitaxel
Carboplatin
Etoposide
Capecitabine
Diethylstilbestrol
Gemcitabine
Cyclophosphamide
Estramustine
Pamidronate
5-Fluorouracil
Cyproterone
Methotrexate
Pirarubicin
Vinblastine
Abbreviation: IRMA = Renal Insufficiency and Anticancer Medications
82 (46.9)
19 (10.9)
17 (9.7)
14 (8.0)
7 (4.0)
7 (4.0)
5 (2.9)
4 (2.3)
3 (1.7)
3 (1.7)
3 (1.7)
2 (1.1)
2 (1.1)
2 (1.1)
1 (0.6)
1 (0.6)
1 (0.6)
1 (0.6)
1 (0.6)
Need for
Dosage
AdjustmentAdjustment
Need for
Dosage
Yes
Yes
Yes
No
Yes
No
Yes
Yes
Yes
No data
No
Yes
No data
No data
No
No data
Yes
No data
No
Potential
Nephrotoxicity Nephrotoxicity
Potential
No
Yes
No
No
Yes
Yes (isolated cases)
Yes
No
No
No
Yes
No
Yes
Yes
No
No
Yes
Yes (isolated cases)
No
Drug (%)Drug (%)
Number of
Prescriptions
(n = 53) (n = 53)
Number of
Prescriptions
IRMA Study: Anticancer Drugs Prescribed to 38
Patients With Prostate Cancer Without Bone Metastases
Table 7
Docetaxel
Vinorelbine
Bicalutamide
Mitoxantrone
Carboplatin
Gemcitabine
Leuprorelin
Goserelin
Cisplatin
Etoposide
5-Fluorouracil
Triptorelin
Capecitabine
Nilutamide
Pirarubicin
Irinotecan
Oxaliplatin
Abbreviation: IRMA = Renal Insufficiency and Anticancer Medications
17 (32.1)
4 (7.5)
4 (7.5)
3 (5.7)
3 (5.7)
3 (5.7)
3 (5.7)
3 (5.7)
2 (3.8)
2 (3.8)
2 (3.8)
2 (3.8)
1 (1.9)
1 (1.9)
1 (1.9)
1 (1.9)
1 (1.9)
Need for
Dosage
AdjustmentAdjustment
Need for
Dosage
Yes
Yes
No
No
Yes
No
No data
No data
Yes
Yes
No
No data
Yes
Yes
No data
No data
No
Potential
NephrotoxicityNephrotoxicity
Potential
No
No
No
No
Yes
Yes
No
No
Yes
No
No
No
No
Yes
Yes (isolated cases)
Yes
Yes
Clinical Genitourinary Cancer October 2009 • E87
Vincent Launay-Vacher et al

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Prostate Cancer and Renal Insufficiency
E88 • Clinical Genitourinary Cancer October 2009
(25.4%) and, thus, was a concern for only 29.1% of the patients.
There were significantly more prescriptions of anticancer drugs
necessitating dosage adjustment in RI (P = .001) and significantly
more patients prescribed such drugs (P = .01) in the patients with
prostate cancer and BM compared with those without BM
(Tables 6-8). There was no significant difference between the 2
groups regarding nephrotoxic drugs because most of the drugs used
were not toxic to the kidneys.
The IRMA study did not allow evaluation of the potential cause
of decreased renal function in our patients besides age, which was
somehow elevated (67.7 years). Other causes must, however, be
considered. For instance, the frequent administration of contrast
media for computed tomography scan, which is known to be a
potential cause of renal dysfunction, might be 1 of the etiologies in
addition to or rather than chemotherapy.
Depending on the level of the renal function of the patient once
in remission, twice-a-year monitoring might be sufficient during
follow-up; under treatment, patients should be monitored for renal
function at each course of therapy. Furthermore, in the patients
who require a nephrotoxic antineoplastic chemotherapy, especially
those with baseline decreased renal function, cautious selection and
analysis of associated drugs should be performed. For example, non-
steroidal anti-inflammatory drugs should be avoided when possible
because they might potentate the renal toxicity of chemotherapy.
Regarding the treatment of BM, when a bisphosphonate is to be
prescribed, the same selection rules should be applied according to
renal tolerance and dosage adjustment. There are no specific limita-
tions in the use of bisphosphonates in the elderly. Task forces from
the International Society of Geriatric Oncology recommended a
monitoring of CrCl, preferably before each course, in every patient;
the use of an agent with the best possible renal tolerability; and the
assessment of hydration status.14-16
In patients with evidence of renal deterioration during treatment,
intravenous bisphosphonates should be withheld and only resumed
when SCr returns to within 10% of baseline.17 In case of mild-to-
moderate renal impairment (CrCl 30-60 mL/minute), regulations
recommend lower doses of zoledronate and longer infusion for
pamidronate. Treatment with zoledronate is contraindicated in pa-
tients with severe dysfunction (CrCl < 30 mL/minute).
A recent label of ibandronate approved by European regulatory
authorities allows a dosing regimen of 6 mg over 60 minutes in-
stead of 15 minutes when CrCl is 30-50 mL/minute. Furthermore,
a dose reduction has been recommended for ibandronate (2 mg
instead of 6 mg) for patients with CrCl < 30 mL/minute.15 Oral
bisphosphonates might be an option of choice because they are well
tolerated renally.
Conclusion
In the IRMA study, the high prevalence of RI has been
evidenced, and in this subgroup analysis of patients with prostate
cancer, the prevalence is confirmed as high. In all patients, renal
function should no more be evaluated only on the value of SCr, but
also on an estimate of renal function, calculated with the Cockcroft-
Gault or the aMDRD formula. The anticancer drugs used in those
patients were not nephrotoxic for their majority, but they however
need a dosage adjustment in case of RI. As a result, in order to avoid
overdose and toxicity, renal function must be estimated routinely on
a regular basis, and drugs dosages should be carefully adjusted to the
level of renal function when RI is diagnosed.
Acknowledgments
Under the direction of the IRMA Scientific Committee, the
IRMA Study has been coordinated by ICAR, a National Medical
Advisory Service on the interactions between drugs and the kidney
(ie, drug dosage adjustment, drug nephrotoxicity, drug-drug inter-
actions with immunosuppressive therapies) located in the Depart-
ment of Nephrology at Pitié-Salpêtrière Hospital in Paris, France.
The authors are indebted to the physicians who took time from
their busy work schedules to participate in the IRMA Study Group
and to Roche France, thanks to whom ICAR services are available to
French oncologists through an unrestricted educational grant.
IRMA Scientific Committee Members (Alphabetical)
P. Beuzeboc, Paris; G. Deray, Paris; J. Gligorov, Paris; V. Lau-
nay-Vacher, Paris; J.-F. Morere, Paris; S. Oudard, Paris; X. Pourrat,
Tours; I. Ray-Coquard, Lyon, J.-P. Spano, Paris
IRMA Study Group Members (Alphabetical)
Pr A. Adenis, Lille; Dr E. Banu, Paris; Dr P. Beuzeboc, Paris; Dr
H. Boostandoost, Paris; Dr S. Clisant, Lille; Dr N. Colbert, Paris;
Dr L-M. Dourthe, Metz; Dr D. Egret, Nantes; Dr J. Egreteau, Lori-
PopulationPopulation
Prescription Pattern of Drugs That Necessitate Dosage
Adjustment or Might Be Nephrotoxic in Patients With
Prostate Cancer With or Without Bone Metastases
Table 8
Prescriptions (%)
Dosage adjustment
in renal insufficiency
Yes
No data
No
Nephrotoxicity
Yes
No data
No
Treated Patients (%)
Dosage adjustment
in renal insufficiency
Yes
No data
No
Nephrotoxicity
Yes
No data
No
Patients With
Bone MetastasesBone Metastases
Patients With
(n = 175)
140 (80.0)
9 (5.1)
26 (14.9)
47 (26.9)
0
128 (73.1)
(n = 137)
115 (83.9)
4 (2.9)
18 (13.1)
42 (30.7)
0
95 (69.3)
Patients Without
Bone MetastasesBone Metastases
Patients Without
(n = 53)
30 (56.6)
10 (18.9)
13 (24.5)
12 (22.6)
0
41 (77.4)
(n = 38)
23 (60.5)
10 (26.3)
5 (13.2)
9 (23.7)
29 (76.3)
P Value
P Value
.001
.5
.01
.4

Page 7

ent; Dr J. Gligorov, Paris; Dr J-P. Guastalla, Lyon; Dr M-F. Jaeger,
Metz; Dr F. Joly, Caen; Dr J. Ayllon, Paris; Dr C. Le Tourneau,
Paris; Dr C.-B. Levache, Périgueux; Dr A. Lortholary, Nantes;
Mr C. Maguire, Périgueux; Dr A. Monnier, Montbéliard; Pr J-F.
Morere, Paris; Dr E. Ouahrani, Paris; Pr S. Oudard, Paris; Dr I.
Ray-Coquard, Lyon; Pr O. Rixe, Paris; Dr E. Sevin, Caen; Dr L.
Stefani, Grenoble, France
Disclosures
The authors have no relevant relationships to disclose.
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