Lung (2009) 187:69–74 DOI 10.1007/s00408-008-9123-5
Lung Cancer and Renal Insufficiency: Prevalence and Anticancer Drug Issues Vincent Launay-Vacher Æ Reza Etessami Æ Nicolas Janus Æ Jean-Philippe Spano Æ Isabelle Ray-Coquard Æ Ste´phane Oudard Æ Joseph Gligorov Æ Xavier Pourrat Æ Philippe Beuzeboc Æ Gilbert Deray Æ Jean-Franc¸ois Morere Æ The Renal Insufficiency Anticancer Medications (IRMA) Study Group
Received: 26 July 2008 / Accepted: 19 September 2008 / Published online: 22 October 2008 Ó Springer Science+Business Media, LLC 2008
Abstract The Renal Insufficiency and Anticancer Medications (IRMA) study reported the high prevalence of renal insufficiency in cancer patients. In this special report, we focused on patients with lung cancer, emphasizing some specific findings in this population of patients. Data on patients with lung cancer who were in 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 renal insufficiency (RI) according to the KDOQIKDIGO definition. Anticancer drugs were studied with regard to their potential renal toxicity and need for dosage adjustment. Of the 445 IRMA lung cancer patients, 14.4% had a serum creatinine (SCR) level C110 lmol/L. However, when they were assessed using the formulas, 62.1 and 55.9% had abnormal renal function. Of the 644 anticancer drug prescriptions, 67.5% required dose adjustments for RI
or were drugs with no available data, and 78.3% of the patients received at least one such drug. Furthermore, 71.6% received potentially nephrotoxic drugs. Seventy percent of the patients had anemia but prevalence was not significantly associated with the existence of associated renal insufficiency. In the 445 IRMA patients with lung cancer, the prevalence of RI was high in spite of a normal SCR in most cases. Some anticancer drugs such as platinum salts may be nephrotoxic and need dosage adjustment. However, other important drugs such as gemcitabine do not require dose reduction and do not present with a high potential for nephrotoxicity. Lung cancer patients often present with anemia, which was not associated with the presence of RI. Keywords Lung cancer Renal insufficiency Anemia Dosage adjustment Nephrotoxicity
The IRMA study group is based in Department of Nephrology, Pitie Salpetriere Hospital, Paris, France. V. Launay-Vacher (&) N. Janus G. Deray Department of Nephrology, Pr. Deray, Hoˆpital Pitie´-Salpeˆtrie`re, 47-83 Boulevard de l’Hoˆpital, 75013 Paris, France e-mail:
[email protected] R. Etessami J.-F. Morere Department of Medical Oncology, Hoˆpital Avicenne, Bobigny, France J.-P. Spano Department of Medical Oncology, Hoˆpital Pitie´-Salpeˆtrie`re, Paris, France
S. Oudard Department of Medical Oncology, Hoˆpital Europe´en Georges Pompidou, Paris, France J. Gligorov Department of Medical Oncology, Hoˆpital Tenon, Paris, France X. Pourrat Department of Clinical Pharmacy, Hoˆpital Trousseau, Tours, France P. Beuzeboc Department of Medical Oncology, Institut Curie, Paris, France
I. Ray-Coquard Department of Medical Oncology, Centre Le´on Be´rard, Lyon, France
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Introduction The increased incidence of malignancies in patients with chronic renal failure has been discussed since the mid1970s [1, 2]. In their study, Cengiz et al. [3] reported that 188 (6.7%) organ tumors of varying pathologies were found in 2817 patients with chronic renal failure. Although it is known to be a common pathology in the general population [4], the prevalence of renal insufficiency (RI) among patients with cancer has only been recently assessed in the Renal Insufficiency and Anticancer Medications (IRMA) study [5], where we found a high prevalence of RI among 4684 solid tumor patients from 15 French cancer centers. Only 7.2% had elevated serum creatinine (SCR) but 50–60% had creatinine clearance below 90 ml/min, which defines a stage 2 kidney disease according to the K/ DOQI-KDIGO official international definition [6, 7]. ‘‘Renal insufficiency’’ defines a reduction in renal function. This can also be found in the literature as ‘‘renal failure.’’ However, in the international definition from the KDOQI-KDIGO, ‘‘kidney failure’’ is the terminology used to describe a stage 5 kidney disease. Therefore, ‘‘renal failure’’ should not be used to describe a reduction in renal function. It should be used only for patients with a stage 5 kidney disease, formerly also called end-stage renal disease. This high prevalence of RI is an important issue the handling of anticancer drugs in RI patients. Because approximately half 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 will, therefore, frequently need to be reduced to avoid severe toxicities. Furthermore, using potentially nephrotoxic anticancer drugs will also require specific monitoring and, when available, specific prevention methods to help reduce the risk for renal toxicity, especially in patients with baseline abnormal renal function before anticancer therapy is started. In this article we present the results from the analysis of the subgroup of 445 lung cancer patients in the IRMA population.
Methods Study Design for the IRMA Study The IRMA study included 4684 patients being treated for solid tumors (either in hospital or as outpatients) in an oncology department. The study consisted of a retrospective patient data collection in one of two specific 15-day time periods either between the 1st and the 15th of
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February 2004 or between the 1st and the 15th of October 2004. These time periods were selected to avoid summer vacations and to be representative of the whole year, with one period in winter/spring and the other 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 under 18 years of age, had a diagnosis of myeloma, or presented with endstage renal disease requiring renal replacement therapy (either hemodialysis or peritoneal dialysis). The following data were collected for each patient: gender, age, weight, serum creatinine, 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 calculation from SCR using the Cockcroft–Gault formula [8] and the abbreviated Modification of Diet in Renal Disease (aMDRD) formula [9]. Cockcroft–Gault formula: CrCl ðml=minÞ ¼ k ½ð140 ageÞ weight ðkgÞ=SCRðlmol=lÞ where k = 1.23 (male) or 1.04 (female), CrCl is creatinine clearance, and SCR is serum creatinine. aMDRD formula: GFR ml=min=1:73 m2 ¼ k 186 ½SCR1:154 ½age0:203 where k = 1 (male) or 0.742 (female), GFR is glomerular filtration rate, and SCR is serum creatinine (mg/dl). Renal function, calculated using either formula, was staged in accordance with the international clinical practice guidelines from the K/DOQI and the KDIGO [6, 7]: Stage Stage Stage Stage Stage
1: 2: 3: 4: 5:
GFR C 90 ml/min GFR = 60–89 ml/min GFR = 30–59 ml/min GFR = 15–29 ml/min GFR \ 15 ml/min
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 from two reference books on drug dosage adjustment in patients with RI [10, 11]. Anticancer therapies were then classified as ‘‘Yes’’ when adjustment was required, ‘‘No’’ when adjustment was not necessary, and ‘‘ND’’ when no data were available in the literature. To obtain profiles of anticancer therapies with regard to renal tolerance, an exhaustive literature
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search was performed using PubMed 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 ‘‘potentially nephrotoxic.’’ Therapies were labeled ‘‘No’’ when no cases had been found or there were no suggestions of potential renal toxicity.
Results of the Lung Cancer Subgroup Analysis Patient Demographics A total of 445 patients with lung cancer were included in the study. Of these, 313 patients were men leading to a M/F ratio of 2.37, and the mean age of all patients was 61.1 years.
Anemia Anemia, according to the WHO definition (\12 g/dl in women and \13 g/dl in men), was observed in 66.3% of IRMA lung cancer patients. Further analysis showed that 4.9 and 23.8% of the patients had a hemoglobin level lower than 9 g/dl and within 9–11 g/dl, respectively. For 4.7%, no hemoglobin value was available in the medical file of the patient. Comparing men and women, the prevalence of anemia was about the same, i.e., 31.1 and 27.8% for women and men, respectively, with a hemoglobin value lower than 11 g/dl. The prevalence of anemia as defined by the WHO was studied in patients with RI versus patients without RI. RI was defined according to Cockcroft–Gault to be lower than 90 or 60, and according to aMDRD lower than 90 or 60. Results are presented in Table 2 and 3. Anticancer Drugs
Renal Insufficiency Table 1 shows the percentages of patients among the five stages of RI. Among the whole population of lung cancer patients, only 64 (14.4%) had a SCR level C110 lmol/L. Of notice are the 5.1% of patients for whom no SCR could be retrieved in the medical file. In spite of this low proportion of patients with elevated SCR, a majority of patients had in fact a decreased CrCl or eGFR; 62.1 and 55.9% of patients had abnormal renal function (\90 ml/ min) when calculated using the Cockcroft–Gault or aMDRD formula, respectively (Table 1). This high prevalence of RI was also observed in the 358 patients (80.4%) whose SCR levels were normal, i.e., \110 lmol/L; 60.1 and 51.7% of those patients had abnormal renal function (\90 ml/min) when calculated using the Cockcroft–Gault or aMDRD formula, respectively.
Table 1 Renal function of the 445 IRMA patients with lung cancer determined using the Cockcroft–Gault and the aMDRD formulas Cockcroft–Gault CrCl (ml/min)
aMDRD eGFR (ml/min/1.73 m2)
N
%
N
%
C90
138
31.0
173
38.9
89–60
172
38.6
173
38.9
59–30
95
21.4
73
16.4
29–15
9
2.0
3
0.7
\15
0
0
0
0
ND
31
7.0 100%
23
5.1 100%
CrCl = creatinine clearance; eGFR = estimated glomerular filtration rate; N = number of patients
Among the whole study population of 445 lung cancer patients, 85.8% were receiving anticancer drugs during the time period studied. This resulted in 382 treated patients for a total number of anticancer drug prescriptions of 644, i.e., 1.7 drugs/patient. The prescriptions comprised 26 different drugs according to their International Non-proprietary Name (INN) (Table 4), of which 53.8% are drugs that necessitate dosage adjustment in RI and 23.1% are
Table 2 Prevalence of anemia in patients with RI compared to patients without RI (Cockcroft–Gault) Prevalence of anemia N (%) Cockcroft–Gault
\90 (N = 271)
[90 (N = 135)
Nonanemic
80 (29.5%)
42 (31.1%)
Anemic
191 (70.5%)
93 (68.9%)
Cockcroft–Gault
\60 (N = 103)
[60 (N = 303)
Nonanemic
31 (30.1%)
91 (30.0%)
Anemic
72 (69.9%)
212 (70.0%)
P [ 0.05
P [ 0.05
RI = renal insufficiency
Table 3 Prevalence of anemia in patients with RI compared to patients without RI (aMDRD) Prevalence of anemia N (%) aMDRD Nonanemic
\90 (N = 245) 75 (30.6%)
[90 (N = 169) 51 (30.2%)
Anemic
170 (69.4%)
118 (69.8%)
aMDRD
\60 (N = 75)
[60 (N = 339)
Nonanemic
21 (28%)
105 (31.0%)
Anemic
54 (72.0%)
234 (69.3%)
P [ 0.05
P [ 0.05
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72 Table 4 Anticancer drugs prescribed to lung cancer patients in the IRMA study (382 treated patients and 644 prescriptions)
INN = International Nonproprietary Name; ND = No data; 5-FU = 5-fluorouracil
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INN
No. of prescriptions
% of the total no. of prescriptions
Need for dosage adjustment
Potential nephrotoxicity
Gemcitabine
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18.9
No
Yes
Carboplatin
108
16.8
Yes
Yes
Cisplatin
105
16.3
Yes
Yes
Vinorelbine
70
10.9
Yes
No
Docetaxel
60
9.3
Yes
No
Paclitaxel
60
9.3
No
Yes
Etoposide
41
6.4
Yes
No
5-FU
9
1.4
No
No
Irinotecan
9
1.4
ND
Yes
Doxorubicin
9
1.4
No
Yes
Ifosfamide Oxaliplatin
9 8
1.4 1.2
Yes No
Yes Yes
Zoledronate
8
1.2
Yes
Yes
Pemetrexed
7
1.1
Nd
Yes
Mitomycin C
4
0.6
Yes
Yes
Capecitabine
2
0.3
Yes
No
Gefitinib
2
0.3
Nd
Yes
Topotecan
2
0.3
Yes
Yes
Vinflunine
2
0.3
ND
Nd
Cytarabine
1
0.2
Yes
Yes
Cyclophosphamide
1
0.2
Yes
No
Cetuximab
1
0.2
ND
Yes
Exemestan
1
0.2
No
No
Methotrexate
1
0.2
Yes
Yes
Raltitrexed
1
0.2
Yes
No
Trastuzumab
1
0.2
ND
Yes
drugs for which no data were available in the literature on whether it would be necessary to adjust their dosage in case of renal impairment. Of the 644 prescriptions, 67.5% were for drugs for which a dosage adjustment was necessary or for which there were no available data concerning administration in patients with RI, 64.1 and 3.4%, respectively. Finally, 78.3% of the patients were receiving at least one drug that necessitates dosage adjustment in RI and 2.3% were receiving at least one drug for which no data were available, resulting in a total 80.6% of lung cancer patients in IRMA with at least one drug for which caution is mandatory in RI (either dosage adjustment required or no data available). Regarding nephrotoxicity, 69.2% of the drugs were potentially toxic to the kidneys (65.4%) or were drugs for which there were no data in the literature on their renal tolerance (3.8%). Among the prescriptions, 71.3% were prescriptions of drugs that may be nephrotoxic, and 71.6% of lung cancer patients in IRMA were receiving at least one drug that may exhibit renal toxicity.
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Discussion In this study we found that RI is highly prevalent in lung cancer patients. In fact, only approximately one third of our 445 lung cancer patients had normal renal function (31 and 38.9% with Cockcroft–Gault and MDRD, respectively). However, the frequency of RI clearly is routinely underestimated in clinical practice because physicians most often base their diagnosis on SCR measurements. It is crucial to point out that SCR is not appropriate for evaluating renal function. It is therefore of crucial importance that renal function be evaluated with the appropriate tools in all patients, including lung cancer patients, by estimating CrCl or GFR calculated using either the Cockcroft–Gault or the aMDRD formula. This includes patients who have normal SCR levels because even in those lung cancer patients whose serum creatinine levels were within the normal range, RI was actually observed in more than half of the patients. Furthermore, no estimation of renal function could be made with the Cockcroft–Gault formula in 7% of
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our patients and with the aMDRD formula in 5.1% due to a lack of data on SCR and/or the weight of the patient in the medical file. This is an issue that can easily be corrected; it is clearly important that those data be reported in the medical records of each cancer patient. To date there are no data about recommending the use of one formula over the other, for oncology patients and the general population. Most often, differences between the two formulas in terms of renal function are weak. Some differences may be observed in the range of patients in the different stages of RI. However, when the Cockcroft–Gault and the aMDRD estimates differ for a particular patient, it may be useful to measure the actual GFR after discussing it with a nephrologist. GFR measurements include a 24-h urine collection to measure creatinine clearance or a measure of the actual GFR using a specific marker of renal filtration such as inulin, iothalamate, or 51CR-EDTA, for instance. However, such methods necessitate a trained staff, time, and are not cost-effective for a systematic evaluation of a patient’s renal function. They must be used only in specific cases, and patients who may benefit from such a determination of renal function should be identified with help from a nephrologist, according to the patient’s profile, and the estimated renal function determined from Cockcroft–Gault and aMDRD. In patients with stage 2 RI, which represented 38.6 and 38.9% of our patients according to Cockcroft–Gault and aMDRD, respectively, potential drug nephrotoxicity is the main issue. Many studies have demonstrated that preexisting abnormal renal function is a risk factor for druginduced nephrotoxicity [12]. As a result, in those patients with mildly decreased renal function, anticancer drugs, antineoplastic or supportive care, should be selected carefully so as to find those that are not or are less nephrotoxic. When renal function is less than 60 ml/min, which was the case for approximately 20% of our patients (23.4% with Cockcroft–Gault and 17.1% with aMDRD), the risk for nephrotoxicity is even higher, and 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 overdose due to accumulation of the drug from reduced excretion and related toxicities, i.e., neurologic, hematologic, skeletal, cardiologic, and hepatologic. Indeed, when renal function declines and is lower than 60 ml/min, pharmacokinetic changes necessitate modification of the drug dosage to ensure efficacy and safety. Over 80% of lung cancer patients in the IRMA population received at least one 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). In patients who are
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receiving drugs that require dosage adjustment, renal function should be calculated (with Cockcroft–Gault or aMDRD) so as to prescribe drugs at their adjusted dosage in accordance with their renal function, preferably before each course of anticancer therapy, chemotherapy, or other type of treatment. Where information is not available on dosage adjustments in patients with RI, the oncologist in charge of the patient should discuss the prescription of these drugs with a pharmacologist or a nephrologist. When an alternative treatment exists for which recommendations are available, it is preferred that it be used. 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 IRMA lung cancer patients the frequency of nephrotoxic drug prescriptions was high, with 71.6% of the whole population and 83.5% of the treated patients receiving at least one such drug. When one such drug is to be prescribed in a patient with lung cancer, for instance, cisplatin, an accurate evaluation of renal function must be performed before administration of the drug. In all cases, but especially when renal function is abnormal (estimate below 90), specific procedures to optimize renal tolerance must be used when they exist. In some cases, such as for cisplatin, guidelines are available in the literature [13]. In those patients, and moreover in every patient, especially for those older than 70, renal function must be estimated prior to each course of cancer therapy. In general, once a patient is diagnosed with decreased renal function, drug therapy should be reevaluated, dosages adjusted where necessary, and some potentially nephrotoxic drugs changed for less or non-nephrotoxic drugs when efficacy has been proven to be similar. Depending on the level of renal function of the patient once in remission, monitoring twice a year may be sufficient during follow-up. In our patients, anemia as defined by the WHO was frequently present, with 57.6% of women presenting with a hemoglobin level lower than 12 g/dl and 70% of men with a value below 13 g/dl. Severe anemia was highly in our study population, with 28.7% presenting with a hemoglobin level below 11 g/dl (4.9% below 9 g/dl and 23.8% between 9 and 11 g/dl). Patients with lung cancer are known to have several conditions which may favor the development of anemia such as their age, the potentially hematotoxic drugs they receive, and the lung cancer disease itself. However, it is well known that RI may also induce anemia. Furthermore, considering the high prevalence of RI in our patients with lung cancer, the lack of diagnosis when it was based only on SCR, and the frequent necessity to adjust drug dosage in those patients, we postulated that RI may be one additional cause of anemia in our patients. We thus studied the differences in the
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prevalence of anemia in our patients according to their renal function with four different criteria for the definition of RI: a Cockcroft–Gault estimate below 90 or 60, and a aMDRD estimate below 90 or 60 (Tables 2 and 3). However, we found no statistically significant difference between those different groups of patients in the prevalence of anemia (WHO definition), which was in all cases around 70%. This result suggests that although RI is highly prevalent, renal disease does not seem to influence the prevalence of anemia in our patients. There are, however, some limitations to this observation because the number of patients differed in the groups due to the high frequency of anemia. In addition, in a recent article by McFarlane et al. [14] from the KEEP program (Kidney Early Evaluation Program), the prevalence of anemia, as defined by the WHO, was stable and around 20% in patients with a stage 1–3 RI, and then it increases up to 60–70% of patients with stage 4–5 RI. In our 445 patients, only 9 had stage 4–5 RI, i.e., a renal function estimate below 30 ml/min determined with Cockroft–Gault and 3 ml/min determined with aMDRD. This low number of patients with stage 4–5 RI may explain why we found no influence of RI on the prevalence of anemia in our patients.
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2.
3.
4.
5.
6.
7.
8. Acknowledgment 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 (i.e., drug dosage adjustment, drug nephrotoxicity, drug-drug interactions with immunosuppressive therapies), located in the Department of Nephrology at Pitie´-Salpeˆtrie`re 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 (in alphabetical order): P. Beuzeboc, Paris; G. Deray, Paris; J. Gligorov, Paris; V. Launay-Vacher, Paris; J.-F. Morere, Paris; S. Oudard, Paris; X. Pourrat, Tours; I. RayCoquard, Lyon, J.-P. Spano, Paris. IRMA Study Group (in alphabetical order): 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, Lorient; 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, Pe´rigueux; Dr A. Lortholary, Nantes; Mr C. Maguire, Pe´rigueux; Dr A. Monnier, Montbe´liard; Pr J-F. Morere, Paris; Dr E. Ouahrani, Paris; Pr S. Oudard, Paris; Dr I. RayCoquard, Lyon; Pr O. Rixe, Paris; Dr E. Sevin, Caen; Dr L. Stefani, Grenoble, France.
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