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Renal Function After Nephron-sparing Surgery Versus Radical Nephrectomy: Results from EORTC Randomized Trial 30904
EURURO-5191; No. of Pages 6 EUROPEAN UROLOGY XXX (2013) XXX–XXX
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Renal Function After Nephron-sparing Surgery Versus Radical Nephrectomy: Results from EORTC Randomized Trial 30904 Emil Scosyrev a, Edward M. Messing a,*, Richard Sylvester b, Steven Campbell c, Hendrik Van Poppel d a
Department of Urology, University of Rochester Medical Center, Rochester, NY, USA; b Department of Biostatistics, EORTC Headquarters, Brussels, Belgium;
c
Department of Urology, Cleveland Clinic, Cleveland, OH, USA; d Department of Urology, University Hospital K.U. Leuven, Leuven, Belgium
Article info
Abstract
Article history: Accepted June 21, 2013 Published online ahead of print on July 2, 2013
Background: In the European Organization for Research and Treatment of Cancer (EORTC) randomized trial 30904, nephron-sparing surgery (NSS) was associated with reduced overall survival compared with radical nephrectomy (RN) over a median follow-up of 9.3 yr (hazard ratio: 1.50; 95% confidence interval [CI], 1.03–2.16). Objective: To examine the impact of NSS relative to RN on kidney function in EORTC 30904. Design, setting, and participants: This phase 3 international randomized trial was conducted in patients with a small (5 cm) renal mass and normal contralateral kidney who were enrolled from March 1992 to January 2003. Intervention: Patients were randomized to RN (n = 273) or NSS (n = 268). Outcome measurements and statistical analysis: Follow-up estimated glomerular filtration rates (eGFR; milliliters per minute per 1.73 m2) were recorded for 259 subjects in the RN arm and 255 subjects in the NSS arm. Percentages of subjects developing at least moderate renal dysfunction (eGFR <60), advanced kidney disease (eGFR <30), or kidney failure (eGFR <15) were calculated for each treatment arm based on the lowest recorded follow-up eGFR (intent-to-treat analysis). Results and limitations: With a median follow-up of 6.7 yr, eGFR <60 was reached by 85.7% with RN and 64.7% with NSS, with a difference of 21.0% (95% CI, 13.8–28.3); eGFR <30 was reached by 10.0% with RN and 6.3% with NSS, with a difference of 3.7% (95% CI, –1.0 to 8.5); and eGFR <15 was reached by 1.5% with RN and 1.6% with NSS, with a difference of –0.1% (95% CI, –2.2 to 2.1). Lack of longer follow-up for eGFR is a limitation of these analyses. Conclusions: Compared with RN, NSS substantially reduced the incidence of at least moderate renal dysfunction (eGFR <60), although with available follow-up the incidence of advanced kidney disease (eGFR <30) was relatively similar in the two treatment arms, and the incidence of kidney failure (eGFR <15) was nearly identical. The beneficial impact of NSS on eGFR did not result in improved survival in this study population. Registration: EORTC trial 30904; ClinicalTrials.gov identifier NCT00002473. # 2013 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Keywords: Kidney cancer Nephron-sparing surgery Radical nephrectomy
* Corresponding author. Department of Urology, University of Rochester Medical Center, 601 Elmwood Avenue, Box 656, Rochester, NY 14642. Tel. +1 585 275 1321; Fax: +1 585 273 1068. E-mail address: [email protected] (E.M. Messing).
0302-2838/$ – see back matter # 2013 European Association of Urology. Published by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.eururo.2013.06.044
Please cite this article in press as: Scosyrev E, et al. Renal Function After Nephron-sparing Surgery Versus Radical Nephrectomy: Results from EORTC Randomized Trial 30904. Eur Urol (2013), http://dx.doi.org/10.1016/j.eururo.2013.06.044
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1.
Introduction
According to a recent systematic review of 20 observational studies, in patients with a small renal mass (T1a and selected T1b tumors), nephron-sparing surgery (NSS) is associated with improved overall survival compared with radical nephrectomy (RN) [1]. These findings were attributed to similar oncologic outcomes after NSS and RN, with better preservation of renal function after NSS [1]. However, these studies were limited by their observational design and thus subject to selection bias. In 2011, Van Poppel et al. presented results of a randomized trial of NSS versus RN for a small (5 cm) solitary renal mass, with a prospective assessment of renal function, oncologic outcomes, and overall and cause-specific survival [2]. Median follow-up for all-cause mortality was 9.3 yr. In the intention-to-treat analysis, overall survival was better in the RN arm compared with the NSS arm (hazard ratio [HR]:1.50; 95% confidence interval [CI], 1.03–2.16; p = 0.03) [2]. This difference, however, could not be attributed to differences in kidney cancer mortality. Among the 273 patients randomized to RN, 4 patients died from kidney cancer and 46 died from other causes. Among the 268 patients randomized to NSS, 8 patients died from kidney cancer and 59 died from other causes. The difference in kidney cancer mortality (NSS vs RN) was not statistically significant (p = 0.23) [2]. The impact of NSS relative to RN on postoperative kidney function as assessed by the estimated glomerular filtration rate (eGFR) has not been previously reported. The main objective of this analysis was to examine the incidence of at least moderate renal dysfunction (eGFR <60), advanced kidney disease (eGFR <30), and kidney failure (eGFR <15) in the RN and the NSS arms of European Organization for Research and Treatment of Cancer (EORTC) trial 30904. In exploratory analyses, we investigated whether the effect of NSS relative to RN on kidney function depends on baseline creatinine and comorbidities. 2.
Patients and methods
2.1.
Study design
This study was a randomized trial of RN versus NSS, with allcause mortality as the primary end point. Details of the study design were reported elsewhere [2,3]. Eligibility criteria included a solitary renal mass suspicious for renal cell carcinoma 5 cm, a radiographically normal contralateral kidney, and a World Health Organization performance status of 0–2. Preoperative serum creatinine (SC) was documented as 1.25 upper limit of normal (ULN), 1.26–2.5 ULN, or 2.6–5.0 ULN (ie, exact values in milligrams per deciliter or millimoles per liter were not available). Planned postoperative follow-up of patients included SC measurements (in milligrams per deciliter) every 3 mo during the first year, every 4 mo during the second and third years, every 6 mo until the end of the fifth year, and then annually [3]. All patients with at least one postoperative eGFR measurement were included in the current analyses of kidney function. The GFR was estimated according to the
Modification of Diet in Renal Disease 2 (MDRD 2) study equation based on SC, age at the time of SC measurement, sex, and race [4]. Because this equation tends to overestimate GFR with low creatinine values [5], GFR estimates >150 ml/min per 1.73 m2 were set to 150. Written informed consent was obtained from all study participants as previously described [2]. 2.2.
Statistical analysis
The sample size for this trial was determined based on the primary end point of all-cause mortality, as explained elsewhere [2]. Patients were centrally randomized at the EORTC headquarters (with stratification for institution) to undergo RN (n = 273) or NSS (n = 268). Patients were notified of assigned intervention prior to surgery. For the main analyses reported here, subjects were included in the treatment arms to which they were originally assigned (the intent-to-treat principle). However, analyses by treatment received were also performed. In the main set of analyses, we estimated for each treatment arm the percentages of subjects developing at least moderate renal dysfunction stage A (eGFR <60) and stage B (eGFR <45), advanced kidney disease (eGFR <30), or kidney failure (eGFR <15) based on lowest recorded follow-up eGFR [6]. Distributions of the lowest eGFRs were compared between the two treatment arms with the Wilcoxon-Mann-Whitney test [7]. For CIs, the variance of the estimated difference in proportions was estimated by the standard approach (ie, as the sum of the estimated variances of proportions in each treatment arm). These analyses were also repeated by replacing the lowest eGFR with the last eGFR documented for each subject and stratified according to baseline SC (1.25 ULN vs >1.25 ULN) and chronic disease at baseline (any vs none). In additional descriptive analyses, mean eGFR in each treatment arm was computed separately for each year of follow-up by averaging the subject-specific means in a given year of follow-up and plotting these averages against follow-up time. We also defined for each subject an average annual rate of change in eGFR as the slope of the leastsquares line fitted to subject-specific eGFR measurements plotted against follow-up time (in years). The sign of the slope would indicate whether eGFR had a tendency to decrease (negative sign) or increase (positive sign) over time. Distributions of these subject-specific average annual rates were summarized for each treatment arm with medians and first and third quartiles, and compared for significant difference between the arms with the WilcoxonMann-Whitney test [7]. All analyses were performed in SAS v.9.3. All reported p values are two sided. 3.
Results
From March 1992 to January 2003, 541 patients from 45 institutions [2] were randomized to undergo RN (n = 273) or NSS (n = 268). In each intervention arm, 12 patients had no information on follow-up SC and were excluded from the current analyses. Among the remaining patients, the sex of
Please cite this article in press as: Scosyrev E, et al. Renal Function After Nephron-sparing Surgery Versus Radical Nephrectomy: Results from EORTC Randomized Trial 30904. Eur Urol (2013), http://dx.doi.org/10.1016/j.eururo.2013.06.044
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Randomized n = 541 Radical nephrectomy n = 273
Nephron-sparing surgery n = 268
Excluded: No follow-up eGFR (n = 14)
Excluded: No follow-up eGFR (n = 13)
Analyzed n = 259
Analyzed n = 255
Fig. 1 – The Consolidated Standards of Reporting Trials diagram. eGFR = estimated glomerular filtration rate.
Table 1 – Baseline characteristics and administered treatment by assigned treatment
Age, yr, mean (Q1, median, Q3) Sex, n (%) Male Female WHO performance status, n (%) 0 1 2 Chronic disease, n (%) No Cardiovascular Pulmonary Other Serum creatinine, n (%) 1.25 ULN 1.26–2.5 ULN 2.6–5.0 ULN Missing Treatment administered, n (%) RN NSS Missing
Assigned to RN (n = 259)
Assigned to NSS (n = 255)
60.4 (53, 62, 69)
60.9 (53, 62, 69)
171 (66.0) 88 (34.0)
172 (67.5) 83 (32.5)
218 (84.2) 36 (13.9) 5 (1.9)
223 (87.5) 31 (12.1) 1 (0.4)
166 59 13 21
(64.1) (22.8) (5.0) (8.1)
162 53 8 32
(63.5) (20.8) (3.1) (12.6)
242 16 1 0
(93.4) (6.2) (0.4) (0.0)
237 17 0 1
(92.9) (6.7) (0.0) (0.4)
244 (94.2) 14 (5.4) 1 (0.4)
38 (14.9) 217 (85.1) 0 (0.0)
NSS = nephron-sparing surgery; Q1 = first quartile; Q3 = third quartile; RN = radical nephrectomy; ULN = upper limit of normal; WHO = World Health Organization.
two patients in the RN arm and one patient in the NSS arm was unknown. They were also excluded because their eGFR could not be calculated (Fig. 1). Hence the current analyses were based on 259 patients randomized to RN and 255 patients randomized to NSS. Baseline characteristics of these patients and the interventions actually administered are shown in Table 1 (race was not documented, but it is very likely that nearly all subjects were white). In the RN arm, the median number of follow-up eGFR measurements per subject was 9 (first quartile: 5; third quartile: 13), the median time to first eGFR measurement was 3.5 mo (first quartile: 3.0; third quartile: 6.0), and the median time to last eGFR measurement was 6.8 yr (first quartile: 3.6; third quartile: 9.6). In the NSS arm, the median number of follow-up eGFR measurements per subject was 9 (first quartile: 5; third quartile: 13), the median time to first eGFR measurement was 3.5 mo (first quartile: 3.0; third quartile: 5.3), and the median time to last eGFR measurement was 6.5 yr (first quartile: 3.9; third quartile: 9.7). In the NSS arm, five GFR estimates (each in a different patient) exceeded 150 ml/min per 1.73 m2 and were set to 150. In the RN arm, all GFR estimates were <150. Table 2 shows the percentages of subjects reaching different stages of renal dysfunction based on lowest eGFR measurement documented for each subject. Compared with RN, NSS noticeably decreased the percentage of subjects reaching at least moderate renal dysfunction stage A (eGFR <60) and stage B (eGFR <45). The percentage of subjects with advanced kidney disease (eGFR <30) was also lower in the NSS arm, although for this end point, the difference between the two treatment arms was relatively small. The incidence of kidney failure (GFR <15) was nearly identical in the two treatment arms (Table 2). We also performed similar analyses using last eGFR as the end point (Table 2). Based on the analysis of lowest versus last eGFR, some degree of recovery from moderate renal dysfunction (eGFR 30–59) seemed to occur frequently in both treatment arms (Table 2). Nevertheless, based on last eGFR measurement, at least moderate renal dysfunction was still much more common after RN compared with NSS (Table 2). Exploratory analyses of lowest eGFR according to baseline renal function, chronic illness at baseline, and assigned
Table 2 – Analysis of lowest estimated glomerular filtration rate (eGFR) and last eGFR according to specified binary cut-offs, by assigned treatment (median follow-up 6.7 yr) RN (n = 259)
NSS (n = 255)
eGFR
Outcome
No.
%
No.
%
Difference, %
95% CI
p*
Lowest
eGFR eGFR eGFR eGFR eGFR eGFR eGFR eGFR
222 127 26 4 152 64 17 3
85.7 49.0 10.0 1.5 58.7 24.7 6.6 1.2
165 69 16 4 98 34 9 2
64.7 27.1 6.3 1.6 38.4 13.3 3.5 0.8
21.0 21.9 3.7 0.1 20.3 11.4 3.1 0.4
(13.8–28.3) (13.8–30.2) ( 1.0 to 8.5) ( 2.2 to 2.1) (11.8–28.7) (4.7–18.1) ( 0.7 to 6.8) ( 1.3 to 2.1)
<0.001
Last
<60 <45 <30 <15 <60 <45 <30 <15
<0.001
CI = confidence interval; NSS = nephron-sparing surgery; RN = radical nephrectomy. Wilcoxon-Mann-Whitney test.
*
Please cite this article in press as: Scosyrev E, et al. Renal Function After Nephron-sparing Surgery Versus Radical Nephrectomy: Results from EORTC Randomized Trial 30904. Eur Urol (2013), http://dx.doi.org/10.1016/j.eururo.2013.06.044
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Mean eGFR (mg/dl per 1.73 m2)
100 90 80 70 60 50
RN
40
NSS
30 20 10 0 0
No. at risk, RN: No. at risk, NSS:
7
8
224 210 184 166 139 121 97 233 211 183 156 144 118 95
1
2
3
4
5
6
70 73
9 10 11 12 13 14 15 71 63
50 44
32 41
23 21
16 14
11 14
Yr
8 5
Fig. 2 – Mean estimated glomerular filtration rate as a function of time by assigned treatment (vertical bars indicate point-wise 95% confidence intervals). eGFR = estimated glomerular filtration rate; NSS = nephron-sparing surgery; RN = radical nephrectomy.
treatment are summarized in the Appendix. These analyses were limited by small numbers of patients with baseline SC >1.25 ULN. For all eGFR end points, differences between the analyses by treatment assigned and treatment received (not shown) were negligible. Additional descriptive analyses, showing mean eGFR in each treatment arm separately for each year of follow-up, are summarized in Figure 2. During the first year after surgery, mean eGFRs were 52.7 (95% CI, 50.8–54.5) in the RN arm and 66.8 (95% CI, 64.6–68.9) in the NSS arm, a difference of 14.1 ml/min per 1.73 m2. There was no evidence of decline in mean eGFR over time in either arm with available follow-up (Fig. 2), although for individual subjects, average annual rates of change in eGFR varied in magnitude and direction. The medians of the subject-specific annual rates were +0.3 ml/min per 1.73 m2 per year in the RN arm (first quartile: –0.4; third quartile: +1.5) and 0.0 ml/min per 1.73 m2 per year in the NSS arm (first quartile: –1.4; third quartile: +1.2). The rate distributions differed significantly between the arms based on the Wilcoxon-Mann-Whitney test (p = 0.007), with a slight increase in average eGFR in the RN arm and no change in the NSS arm. 4.
Discussion
Our current analyses demonstrated that over a median follow-up of 6.7 yr for eGFR, NSS compared with RN substantially reduced the incidence of at least moderate renal dysfunction stage A (eGFR <60) and stage B (eGFR <45) based on both lowest eGFR and last eGFR, although the incidence of advanced kidney disease (eGFR <30) was relatively similar in the two treatment arms, and the incidence of kidney failure (eGFR <15) was essentially identical. The beneficial impact of NSS on eGFR did not result in improved survival over a median follow-up of 9.3 yr for all-cause mortality (HR: 1.50; 95% CI, 1.03–2.16 in favor of RN, as previously reported) [2]. These findings suggest that
moderate renal dysfunction arising from surgery may not have the same negative implications for overall health as moderate renal dysfunction arising from medical causes such as diabetes or hypertension (medical chronic kidney disease [CKD-M]) [8,9]. Go et al. [8] demonstrated the association of CKD-M with increased mortality in a dose-response fashion (including in persons with eGFR >30). However, it may well be the case that this association is partially or entirely explained by underlying illnesses that affect the kidney, thus causing decline in eGFR, but also directly influence other vital organs. Adjustment for comorbidities did not rule out this explanation because data on the extent of comorbidities were not available [8]. For example, among patients with diabetes, those with a lower eGFR would probably on average have more advanced diabetes. Not surprisingly, these patients would also have higher mortality but not necessarily as a direct consequence of lower eGFR. It is likely that increased cardiovascular and all-cause mortality in persons with CKD-M results from combined effects of systemic illnesses on different organs (ie, excess mortality does not result strictly from the reduced number of nephrons). It should be emphasized that in the study by Go et al., increased mortality in subjects with moderate CKD-M (eGFR 30–59) was seen despite a median follow-up of only 2.84 yr [8]. If these findings were applicable to moderate renal dysfunction arising from surgery, we would expect to see increased mortality in the RN arm of the current trial, since the follow-up for all-cause mortality was much longer (median: 9.3 yr). However, in the current trial, despite significantly lower average eGFR and a much higher incidence of moderate renal dysfunction in the RN arm (Fig. 2 and Table 2), survival was significantly worse in the NSS arm at the conventional level of significance (HR: 1.50; p = 0.03). While this could represent a type I error (ie, the true null of no difference in survival rejected by chance), the observed difference may also represent a true biologic effect.
Please cite this article in press as: Scosyrev E, et al. Renal Function After Nephron-sparing Surgery Versus Radical Nephrectomy: Results from EORTC Randomized Trial 30904. Eur Urol (2013), http://dx.doi.org/10.1016/j.eururo.2013.06.044
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In particular, it may be the case that mechanical and/or ischemic stress on the kidney during NSS may sometimes disrupt the renin-angiotensin system, with long-term consequences for blood pressure regulation. This is speculative but not impossible. However, the immediate differences in renal function between the two groups would indicate that no matter how performed, NSS was done well enough in these patients to preserve some function in the ipsilateral kidney. This finding, as well as the minimal differences in oncologic outcomes, should eliminate serious concern that the NSS was not performed by capable urologic surgeons. Lane et al. recently examined the association of postoperative eGFR after radical or partial nephrectomy with overall survival in a cohort of 4180 patients [10]. They found that in patients who had CKD before surgery, lower postoperative eGFR was associated with increased mortality independent of age and documented comorbidities. However, in patients with normal kidney function prior to surgery, postoperative eGFR was not an independent predictor of survival. These results agree with our current findings because the overwhelming majority of patients in the current trial had no CKD at baseline (Table 1). Similarly, Ibrahim et al. compared kidney function and overall survival of 3698 kidney donors (mean age: 41 yr) to that of the age- sex- and race-matched controls and found no excess risk of endstage kidney disease or all-cause mortality following kidney donation even after 30 yr of follow-up [11]. This again supports the idea that nephron loss by itself may not have a direct influence on survival, except when it is so massive that the eGFR starts approaching the threshold for dialysis or if the kidney function is already significantly impaired at baseline. The main strength of our current study is the randomized treatment assignment. Limitations include lack of detailed information on baseline kidney function (beyond that reported in Table 1) and intermediate-term follow-up for eGFR (median: 6.7 yr). However, because no additional eGFR measurements will be recorded in this trial, no additional analyses of renal function are planned at this time. Although follow-up for all-cause mortality (median: 9.3 yr) was longer than that for eGFR, due to excellent oncologic outcomes most patients (78%) were alive at last follow-up. It is possible that with longer follow-up, the differences seen between the two groups in terms of overall survival might change to some extent. Another limitation of this study is that the target sample size of 1300 patients was not reached because of slow accrual [2]. There was also some degree of imperfect compliance with assigned intervention (Table 1). In subjects assigned to NSS, some crossover (15% in this study) should be expected because tumors that initially appear suitable for NSS may turn out to be more extensive or difficult, thus necessitating a switch to RN. This is a real-world feature and should not necessarily be viewed as a defect of the trial. In subjects assigned to RN, crossover was much less common (5%) than in the NSS arm (Table 1), although arguably this percentage may still be higher than what would be expected in clinical practice after RN has been selected as the first-line therapy. Renal function outcomes when analyzed by treatment
actually received were almost identical to those presented here (intent-to-treat analysis), indicating that crossover did not affect our findings. 5.
Conclusions
In EORTC 30904, the only randomized trial of RN versus NSS completed to date, over a median follow-up of 6.7 yr for eGFR, NSS substantially reduced the incidence of at least moderate renal dysfunction (eGFR <60), although the incidence of advanced kidney disease (eGFR <30) was relatively similar in the two treatment arms and the incidence of kidney failure (eGFR <15) nearly identical. The beneficial impact of NSS on eGFR did not result in improved survival in this study population with a median follow-up of 9.3 yr. Author contributions: Edward M. Messing had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Van Poppel, Sylvester. Acquisition of data: Van Poppel, Sylvester. Analysis and interpretation of data: Scosyrev, Messing, Sylvester, Campbell, Van Poppel. Drafting of the manuscript: Scosyrev. Critical revision of the manuscript for important intellectual content: Messing, Sylvester, Campbell, Van Poppel. Statistical analysis: Scosyrev, Sylvester. Obtaining funding: Van Poppel, Sylvester. Administrative, technical, or material support: None. Supervision: Van Poppel, Sylvester. Other (specify): None. Financial disclosures: Edward M. Messing certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None. Funding/Support and role of the sponsor: This study was supported by Fond Cancer (FOCA) in Belgium. The funding source had no role in the design, conduct, or analysis of this study, interpretation of the data, writing of this paper, or decision to submit it for publication.
Appendix – Analysis of lowest estimated glomerular filtration rate by assigned treatment, with stratification on baseline renal function and chronic disease Outcome BSC 1.25 ULN
BSC >1.25 ULN
No chronic disease
eGFR eGFR eGFR eGFR eGFR eGFR eGFR eGFR eGFR eGFR eGFR eGFR
<60 <45 <30 <15 <60 <45 <30 <15 <60 <45 <30 <15
RN
NSS
p*
207/242 (85.5) 118/242 (48.8) 22/242 (9.1) 4/242 (1.7) 15/17 (88.2) 9/17 (52.9) 4/17 (23.5) 0/17 (0.0) 142/166 (85.5) 71/166 (42.8) 11/166 (6.6) 1/166 (0.6)
151/237 (63.7) 60/237 (25.3) 13/237 (5.5) 3/237 (1.3) 14/17 (82.4) 9/17 (52.9) 3/17 (17.7) 1/17 (5.9) 97/162 (59.9) 39/162 (24.1) 4/162 (2.5) 0/162 (0.0)
<0.001
0.25
<0.001
Please cite this article in press as: Scosyrev E, et al. Renal Function After Nephron-sparing Surgery Versus Radical Nephrectomy: Results from EORTC Randomized Trial 30904. Eur Urol (2013), http://dx.doi.org/10.1016/j.eururo.2013.06.044
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Appendix (Continued ) Outcome Chronic disease
eGFR eGFR eGFR eGFR
<60 <45 <30 <15
nephrectomy for low-stage renal cell carcinoma. Eur Urol 2007; RN
80/93 56/93 15/93 3/93
(86.0) (60.2) (16.1) (3.2)
NSS 68/93 30/93 12/93 4/93
(73.1) (32.3) (12.9) (4.3)
p* 0.003
51:1606–15. [4] Levey AS, Greene T, Kusek J, Beck G. A simplified equation to predict glomerular filtration rate from serum creatinine [abstract]. J Am Soc Nephrol 2000;11:155A. [5] Levey AS, Coresh J, Greene T, et al. Using standardized serum creatinine values in the modification of diet in renal disease study
BSC = baseline serum creatinine; eGFR = estimated glomerular filtration rate, ml/min per 1.73 m2; NSS = nephron-sparing surgery; RN = radical nephrectomy; ULN = upper limit of normal. Data are presented as counts with percentages in parentheses. * Wilcoxon-Mann-Whitney test.
equation for estimating glomerular filtration rate. Ann Intern Med 2006;145:247–54. [6] Levey AS, de Jong PE, Coresh J, et al. The definition, classification, and prognosis of chronic kidney disease: a KDIGO Controversies Conference report. Kidney Int 2011;80:17–28. [7] Desu MM, Raghavarao D. Nonparametric statistical methods for
References
complete and censored data. Boca-Raton, FL: Chapman & Hall/CRC; 2004.
[1] Kim SP, Thompson RH, Boorjian SA, et al. Comparative effectiveness
[8] Go AS, Chertow GM, Fan D, et al. Chronic kidney disease and the
for survival and renal function of partial and radical nephrectomy
risks of death, cardiovascular events, and hospitalization. N Engl J
for localized renal tumors: a systematic review and meta-analysis. J Urol 2012;188:51–7. [2] Van Poppel H, Da Pozzo L, Albrecht W, et al. A prospective randomized EORTC intergroup phase 3 study comparing the oncologic
Med 2004;351:1296–305. [9] Stevens LA, Coresh J, Greene T, Levey AS. Assessing kidney function— measured and estimated glomerular filtration rate. N Engl J Med 2006;354:2473–83.
outcome of elective nephron-sparing surgery and radical nephrec-
[10] Lane BR, Campbell SC, Demirjian S, Fergany AF. Surgically-induced
tomy for low-stage renal cell carcinoma. Eur Urol 2011;59:
chronic kidney disease may be associated with lesser risk of pro-
543–52.
gression and mortality than medical chronic kidney disease. J Urol
[3] Van Poppel H, Da Pozzo L, Albrecht W, et al. A prospective randomized EORTC intergroup phase 3 study comparing the complications of elective nephron-sparing surgery and radical
2013;189:1649–55. [11] Ibrahim HN, Foley R, Tan L, et al. Long-term consequences of kidney donation. N Engl J Med 2009;360:459–69.
Please cite this article in press as: Scosyrev E, et al. Renal Function After Nephron-sparing Surgery Versus Radical Nephrectomy: Results from EORTC Randomized Trial 30904. Eur Urol (2013), http://dx.doi.org/10.1016/j.eururo.2013.06.044
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Platinum Priority – Kidney Cancer Editorial by XXX on pp. x–y of this issue
Renal Function After Nephron-sparing Surgery Versus Radical Nephrectomy: Results from EORTC Randomized Trial 30904 Emil Scosyrev a, Edward M. Messing a,*, Richard Sylvester b, Steven Campbell c, Hendrik Van Poppel d a
Department of Urology, University of Rochester Medical Center, Rochester, NY, USA; b Department of Biostatistics, EORTC Headquarters, Brussels, Belgium;
c
Department of Urology, Cleveland Clinic, Cleveland, OH, USA; d Department of Urology, University Hospital K.U. Leuven, Leuven, Belgium
Article info
Abstract
Article history: Accepted June 21, 2013 Published online ahead of print on July 2, 2013
Background: In the European Organization for Research and Treatment of Cancer (EORTC) randomized trial 30904, nephron-sparing surgery (NSS) was associated with reduced overall survival compared with radical nephrectomy (RN) over a median follow-up of 9.3 yr (hazard ratio: 1.50; 95% confidence interval [CI], 1.03–2.16). Objective: To examine the impact of NSS relative to RN on kidney function in EORTC 30904. Design, setting, and participants: This phase 3 international randomized trial was conducted in patients with a small (5 cm) renal mass and normal contralateral kidney who were enrolled from March 1992 to January 2003. Intervention: Patients were randomized to RN (n = 273) or NSS (n = 268). Outcome measurements and statistical analysis: Follow-up estimated glomerular filtration rates (eGFR; milliliters per minute per 1.73 m2) were recorded for 259 subjects in the RN arm and 255 subjects in the NSS arm. Percentages of subjects developing at least moderate renal dysfunction (eGFR <60), advanced kidney disease (eGFR <30), or kidney failure (eGFR <15) were calculated for each treatment arm based on the lowest recorded follow-up eGFR (intent-to-treat analysis). Results and limitations: With a median follow-up of 6.7 yr, eGFR <60 was reached by 85.7% with RN and 64.7% with NSS, with a difference of 21.0% (95% CI, 13.8–28.3); eGFR <30 was reached by 10.0% with RN and 6.3% with NSS, with a difference of 3.7% (95% CI, –1.0 to 8.5); and eGFR <15 was reached by 1.5% with RN and 1.6% with NSS, with a difference of –0.1% (95% CI, –2.2 to 2.1). Lack of longer follow-up for eGFR is a limitation of these analyses. Conclusions: Compared with RN, NSS substantially reduced the incidence of at least moderate renal dysfunction (eGFR <60), although with available follow-up the incidence of advanced kidney disease (eGFR <30) was relatively similar in the two treatment arms, and the incidence of kidney failure (eGFR <15) was nearly identical. The beneficial impact of NSS on eGFR did not result in improved survival in this study population. Registration: EORTC trial 30904; ClinicalTrials.gov identifier NCT00002473. # 2013 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Keywords: Kidney cancer Nephron-sparing surgery Radical nephrectomy
* Corresponding author. Department of Urology, University of Rochester Medical Center, 601 Elmwood Avenue, Box 656, Rochester, NY 14642. Tel. +1 585 275 1321; Fax: +1 585 273 1068. E-mail address: [email protected] (E.M. Messing).
0302-2838/$ – see back matter # 2013 European Association of Urology. Published by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.eururo.2013.06.044
Please cite this article in press as: Scosyrev E, et al. Renal Function After Nephron-sparing Surgery Versus Radical Nephrectomy: Results from EORTC Randomized Trial 30904. Eur Urol (2013), http://dx.doi.org/10.1016/j.eururo.2013.06.044
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1.
Introduction
According to a recent systematic review of 20 observational studies, in patients with a small renal mass (T1a and selected T1b tumors), nephron-sparing surgery (NSS) is associated with improved overall survival compared with radical nephrectomy (RN) [1]. These findings were attributed to similar oncologic outcomes after NSS and RN, with better preservation of renal function after NSS [1]. However, these studies were limited by their observational design and thus subject to selection bias. In 2011, Van Poppel et al. presented results of a randomized trial of NSS versus RN for a small (5 cm) solitary renal mass, with a prospective assessment of renal function, oncologic outcomes, and overall and cause-specific survival [2]. Median follow-up for all-cause mortality was 9.3 yr. In the intention-to-treat analysis, overall survival was better in the RN arm compared with the NSS arm (hazard ratio [HR]:1.50; 95% confidence interval [CI], 1.03–2.16; p = 0.03) [2]. This difference, however, could not be attributed to differences in kidney cancer mortality. Among the 273 patients randomized to RN, 4 patients died from kidney cancer and 46 died from other causes. Among the 268 patients randomized to NSS, 8 patients died from kidney cancer and 59 died from other causes. The difference in kidney cancer mortality (NSS vs RN) was not statistically significant (p = 0.23) [2]. The impact of NSS relative to RN on postoperative kidney function as assessed by the estimated glomerular filtration rate (eGFR) has not been previously reported. The main objective of this analysis was to examine the incidence of at least moderate renal dysfunction (eGFR <60), advanced kidney disease (eGFR <30), and kidney failure (eGFR <15) in the RN and the NSS arms of European Organization for Research and Treatment of Cancer (EORTC) trial 30904. In exploratory analyses, we investigated whether the effect of NSS relative to RN on kidney function depends on baseline creatinine and comorbidities. 2.
Patients and methods
2.1.
Study design
This study was a randomized trial of RN versus NSS, with allcause mortality as the primary end point. Details of the study design were reported elsewhere [2,3]. Eligibility criteria included a solitary renal mass suspicious for renal cell carcinoma 5 cm, a radiographically normal contralateral kidney, and a World Health Organization performance status of 0–2. Preoperative serum creatinine (SC) was documented as 1.25 upper limit of normal (ULN), 1.26–2.5 ULN, or 2.6–5.0 ULN (ie, exact values in milligrams per deciliter or millimoles per liter were not available). Planned postoperative follow-up of patients included SC measurements (in milligrams per deciliter) every 3 mo during the first year, every 4 mo during the second and third years, every 6 mo until the end of the fifth year, and then annually [3]. All patients with at least one postoperative eGFR measurement were included in the current analyses of kidney function. The GFR was estimated according to the
Modification of Diet in Renal Disease 2 (MDRD 2) study equation based on SC, age at the time of SC measurement, sex, and race [4]. Because this equation tends to overestimate GFR with low creatinine values [5], GFR estimates >150 ml/min per 1.73 m2 were set to 150. Written informed consent was obtained from all study participants as previously described [2]. 2.2.
Statistical analysis
The sample size for this trial was determined based on the primary end point of all-cause mortality, as explained elsewhere [2]. Patients were centrally randomized at the EORTC headquarters (with stratification for institution) to undergo RN (n = 273) or NSS (n = 268). Patients were notified of assigned intervention prior to surgery. For the main analyses reported here, subjects were included in the treatment arms to which they were originally assigned (the intent-to-treat principle). However, analyses by treatment received were also performed. In the main set of analyses, we estimated for each treatment arm the percentages of subjects developing at least moderate renal dysfunction stage A (eGFR <60) and stage B (eGFR <45), advanced kidney disease (eGFR <30), or kidney failure (eGFR <15) based on lowest recorded follow-up eGFR [6]. Distributions of the lowest eGFRs were compared between the two treatment arms with the Wilcoxon-Mann-Whitney test [7]. For CIs, the variance of the estimated difference in proportions was estimated by the standard approach (ie, as the sum of the estimated variances of proportions in each treatment arm). These analyses were also repeated by replacing the lowest eGFR with the last eGFR documented for each subject and stratified according to baseline SC (1.25 ULN vs >1.25 ULN) and chronic disease at baseline (any vs none). In additional descriptive analyses, mean eGFR in each treatment arm was computed separately for each year of follow-up by averaging the subject-specific means in a given year of follow-up and plotting these averages against follow-up time. We also defined for each subject an average annual rate of change in eGFR as the slope of the leastsquares line fitted to subject-specific eGFR measurements plotted against follow-up time (in years). The sign of the slope would indicate whether eGFR had a tendency to decrease (negative sign) or increase (positive sign) over time. Distributions of these subject-specific average annual rates were summarized for each treatment arm with medians and first and third quartiles, and compared for significant difference between the arms with the WilcoxonMann-Whitney test [7]. All analyses were performed in SAS v.9.3. All reported p values are two sided. 3.
Results
From March 1992 to January 2003, 541 patients from 45 institutions [2] were randomized to undergo RN (n = 273) or NSS (n = 268). In each intervention arm, 12 patients had no information on follow-up SC and were excluded from the current analyses. Among the remaining patients, the sex of
Please cite this article in press as: Scosyrev E, et al. Renal Function After Nephron-sparing Surgery Versus Radical Nephrectomy: Results from EORTC Randomized Trial 30904. Eur Urol (2013), http://dx.doi.org/10.1016/j.eururo.2013.06.044
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Randomized n = 541 Radical nephrectomy n = 273
Nephron-sparing surgery n = 268
Excluded: No follow-up eGFR (n = 14)
Excluded: No follow-up eGFR (n = 13)
Analyzed n = 259
Analyzed n = 255
Fig. 1 – The Consolidated Standards of Reporting Trials diagram. eGFR = estimated glomerular filtration rate.
Table 1 – Baseline characteristics and administered treatment by assigned treatment
Age, yr, mean (Q1, median, Q3) Sex, n (%) Male Female WHO performance status, n (%) 0 1 2 Chronic disease, n (%) No Cardiovascular Pulmonary Other Serum creatinine, n (%) 1.25 ULN 1.26–2.5 ULN 2.6–5.0 ULN Missing Treatment administered, n (%) RN NSS Missing
Assigned to RN (n = 259)
Assigned to NSS (n = 255)
60.4 (53, 62, 69)
60.9 (53, 62, 69)
171 (66.0) 88 (34.0)
172 (67.5) 83 (32.5)
218 (84.2) 36 (13.9) 5 (1.9)
223 (87.5) 31 (12.1) 1 (0.4)
166 59 13 21
(64.1) (22.8) (5.0) (8.1)
162 53 8 32
(63.5) (20.8) (3.1) (12.6)
242 16 1 0
(93.4) (6.2) (0.4) (0.0)
237 17 0 1
(92.9) (6.7) (0.0) (0.4)
244 (94.2) 14 (5.4) 1 (0.4)
38 (14.9) 217 (85.1) 0 (0.0)
NSS = nephron-sparing surgery; Q1 = first quartile; Q3 = third quartile; RN = radical nephrectomy; ULN = upper limit of normal; WHO = World Health Organization.
two patients in the RN arm and one patient in the NSS arm was unknown. They were also excluded because their eGFR could not be calculated (Fig. 1). Hence the current analyses were based on 259 patients randomized to RN and 255 patients randomized to NSS. Baseline characteristics of these patients and the interventions actually administered are shown in Table 1 (race was not documented, but it is very likely that nearly all subjects were white). In the RN arm, the median number of follow-up eGFR measurements per subject was 9 (first quartile: 5; third quartile: 13), the median time to first eGFR measurement was 3.5 mo (first quartile: 3.0; third quartile: 6.0), and the median time to last eGFR measurement was 6.8 yr (first quartile: 3.6; third quartile: 9.6). In the NSS arm, the median number of follow-up eGFR measurements per subject was 9 (first quartile: 5; third quartile: 13), the median time to first eGFR measurement was 3.5 mo (first quartile: 3.0; third quartile: 5.3), and the median time to last eGFR measurement was 6.5 yr (first quartile: 3.9; third quartile: 9.7). In the NSS arm, five GFR estimates (each in a different patient) exceeded 150 ml/min per 1.73 m2 and were set to 150. In the RN arm, all GFR estimates were <150. Table 2 shows the percentages of subjects reaching different stages of renal dysfunction based on lowest eGFR measurement documented for each subject. Compared with RN, NSS noticeably decreased the percentage of subjects reaching at least moderate renal dysfunction stage A (eGFR <60) and stage B (eGFR <45). The percentage of subjects with advanced kidney disease (eGFR <30) was also lower in the NSS arm, although for this end point, the difference between the two treatment arms was relatively small. The incidence of kidney failure (GFR <15) was nearly identical in the two treatment arms (Table 2). We also performed similar analyses using last eGFR as the end point (Table 2). Based on the analysis of lowest versus last eGFR, some degree of recovery from moderate renal dysfunction (eGFR 30–59) seemed to occur frequently in both treatment arms (Table 2). Nevertheless, based on last eGFR measurement, at least moderate renal dysfunction was still much more common after RN compared with NSS (Table 2). Exploratory analyses of lowest eGFR according to baseline renal function, chronic illness at baseline, and assigned
Table 2 – Analysis of lowest estimated glomerular filtration rate (eGFR) and last eGFR according to specified binary cut-offs, by assigned treatment (median follow-up 6.7 yr) RN (n = 259)
NSS (n = 255)
eGFR
Outcome
No.
%
No.
%
Difference, %
95% CI
p*
Lowest
eGFR eGFR eGFR eGFR eGFR eGFR eGFR eGFR
222 127 26 4 152 64 17 3
85.7 49.0 10.0 1.5 58.7 24.7 6.6 1.2
165 69 16 4 98 34 9 2
64.7 27.1 6.3 1.6 38.4 13.3 3.5 0.8
21.0 21.9 3.7 0.1 20.3 11.4 3.1 0.4
(13.8–28.3) (13.8–30.2) ( 1.0 to 8.5) ( 2.2 to 2.1) (11.8–28.7) (4.7–18.1) ( 0.7 to 6.8) ( 1.3 to 2.1)
<0.001
Last
<60 <45 <30 <15 <60 <45 <30 <15
<0.001
CI = confidence interval; NSS = nephron-sparing surgery; RN = radical nephrectomy. Wilcoxon-Mann-Whitney test.
*
Please cite this article in press as: Scosyrev E, et al. Renal Function After Nephron-sparing Surgery Versus Radical Nephrectomy: Results from EORTC Randomized Trial 30904. Eur Urol (2013), http://dx.doi.org/10.1016/j.eururo.2013.06.044
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Mean eGFR (mg/dl per 1.73 m2)
100 90 80 70 60 50
RN
40
NSS
30 20 10 0 0
No. at risk, RN: No. at risk, NSS:
7
8
224 210 184 166 139 121 97 233 211 183 156 144 118 95
1
2
3
4
5
6
70 73
9 10 11 12 13 14 15 71 63
50 44
32 41
23 21
16 14
11 14
Yr
8 5
Fig. 2 – Mean estimated glomerular filtration rate as a function of time by assigned treatment (vertical bars indicate point-wise 95% confidence intervals). eGFR = estimated glomerular filtration rate; NSS = nephron-sparing surgery; RN = radical nephrectomy.
treatment are summarized in the Appendix. These analyses were limited by small numbers of patients with baseline SC >1.25 ULN. For all eGFR end points, differences between the analyses by treatment assigned and treatment received (not shown) were negligible. Additional descriptive analyses, showing mean eGFR in each treatment arm separately for each year of follow-up, are summarized in Figure 2. During the first year after surgery, mean eGFRs were 52.7 (95% CI, 50.8–54.5) in the RN arm and 66.8 (95% CI, 64.6–68.9) in the NSS arm, a difference of 14.1 ml/min per 1.73 m2. There was no evidence of decline in mean eGFR over time in either arm with available follow-up (Fig. 2), although for individual subjects, average annual rates of change in eGFR varied in magnitude and direction. The medians of the subject-specific annual rates were +0.3 ml/min per 1.73 m2 per year in the RN arm (first quartile: –0.4; third quartile: +1.5) and 0.0 ml/min per 1.73 m2 per year in the NSS arm (first quartile: –1.4; third quartile: +1.2). The rate distributions differed significantly between the arms based on the Wilcoxon-Mann-Whitney test (p = 0.007), with a slight increase in average eGFR in the RN arm and no change in the NSS arm. 4.
Discussion
Our current analyses demonstrated that over a median follow-up of 6.7 yr for eGFR, NSS compared with RN substantially reduced the incidence of at least moderate renal dysfunction stage A (eGFR <60) and stage B (eGFR <45) based on both lowest eGFR and last eGFR, although the incidence of advanced kidney disease (eGFR <30) was relatively similar in the two treatment arms, and the incidence of kidney failure (eGFR <15) was essentially identical. The beneficial impact of NSS on eGFR did not result in improved survival over a median follow-up of 9.3 yr for all-cause mortality (HR: 1.50; 95% CI, 1.03–2.16 in favor of RN, as previously reported) [2]. These findings suggest that
moderate renal dysfunction arising from surgery may not have the same negative implications for overall health as moderate renal dysfunction arising from medical causes such as diabetes or hypertension (medical chronic kidney disease [CKD-M]) [8,9]. Go et al. [8] demonstrated the association of CKD-M with increased mortality in a dose-response fashion (including in persons with eGFR >30). However, it may well be the case that this association is partially or entirely explained by underlying illnesses that affect the kidney, thus causing decline in eGFR, but also directly influence other vital organs. Adjustment for comorbidities did not rule out this explanation because data on the extent of comorbidities were not available [8]. For example, among patients with diabetes, those with a lower eGFR would probably on average have more advanced diabetes. Not surprisingly, these patients would also have higher mortality but not necessarily as a direct consequence of lower eGFR. It is likely that increased cardiovascular and all-cause mortality in persons with CKD-M results from combined effects of systemic illnesses on different organs (ie, excess mortality does not result strictly from the reduced number of nephrons). It should be emphasized that in the study by Go et al., increased mortality in subjects with moderate CKD-M (eGFR 30–59) was seen despite a median follow-up of only 2.84 yr [8]. If these findings were applicable to moderate renal dysfunction arising from surgery, we would expect to see increased mortality in the RN arm of the current trial, since the follow-up for all-cause mortality was much longer (median: 9.3 yr). However, in the current trial, despite significantly lower average eGFR and a much higher incidence of moderate renal dysfunction in the RN arm (Fig. 2 and Table 2), survival was significantly worse in the NSS arm at the conventional level of significance (HR: 1.50; p = 0.03). While this could represent a type I error (ie, the true null of no difference in survival rejected by chance), the observed difference may also represent a true biologic effect.
Please cite this article in press as: Scosyrev E, et al. Renal Function After Nephron-sparing Surgery Versus Radical Nephrectomy: Results from EORTC Randomized Trial 30904. Eur Urol (2013), http://dx.doi.org/10.1016/j.eururo.2013.06.044
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In particular, it may be the case that mechanical and/or ischemic stress on the kidney during NSS may sometimes disrupt the renin-angiotensin system, with long-term consequences for blood pressure regulation. This is speculative but not impossible. However, the immediate differences in renal function between the two groups would indicate that no matter how performed, NSS was done well enough in these patients to preserve some function in the ipsilateral kidney. This finding, as well as the minimal differences in oncologic outcomes, should eliminate serious concern that the NSS was not performed by capable urologic surgeons. Lane et al. recently examined the association of postoperative eGFR after radical or partial nephrectomy with overall survival in a cohort of 4180 patients [10]. They found that in patients who had CKD before surgery, lower postoperative eGFR was associated with increased mortality independent of age and documented comorbidities. However, in patients with normal kidney function prior to surgery, postoperative eGFR was not an independent predictor of survival. These results agree with our current findings because the overwhelming majority of patients in the current trial had no CKD at baseline (Table 1). Similarly, Ibrahim et al. compared kidney function and overall survival of 3698 kidney donors (mean age: 41 yr) to that of the age- sex- and race-matched controls and found no excess risk of endstage kidney disease or all-cause mortality following kidney donation even after 30 yr of follow-up [11]. This again supports the idea that nephron loss by itself may not have a direct influence on survival, except when it is so massive that the eGFR starts approaching the threshold for dialysis or if the kidney function is already significantly impaired at baseline. The main strength of our current study is the randomized treatment assignment. Limitations include lack of detailed information on baseline kidney function (beyond that reported in Table 1) and intermediate-term follow-up for eGFR (median: 6.7 yr). However, because no additional eGFR measurements will be recorded in this trial, no additional analyses of renal function are planned at this time. Although follow-up for all-cause mortality (median: 9.3 yr) was longer than that for eGFR, due to excellent oncologic outcomes most patients (78%) were alive at last follow-up. It is possible that with longer follow-up, the differences seen between the two groups in terms of overall survival might change to some extent. Another limitation of this study is that the target sample size of 1300 patients was not reached because of slow accrual [2]. There was also some degree of imperfect compliance with assigned intervention (Table 1). In subjects assigned to NSS, some crossover (15% in this study) should be expected because tumors that initially appear suitable for NSS may turn out to be more extensive or difficult, thus necessitating a switch to RN. This is a real-world feature and should not necessarily be viewed as a defect of the trial. In subjects assigned to RN, crossover was much less common (5%) than in the NSS arm (Table 1), although arguably this percentage may still be higher than what would be expected in clinical practice after RN has been selected as the first-line therapy. Renal function outcomes when analyzed by treatment
actually received were almost identical to those presented here (intent-to-treat analysis), indicating that crossover did not affect our findings. 5.
Conclusions
In EORTC 30904, the only randomized trial of RN versus NSS completed to date, over a median follow-up of 6.7 yr for eGFR, NSS substantially reduced the incidence of at least moderate renal dysfunction (eGFR <60), although the incidence of advanced kidney disease (eGFR <30) was relatively similar in the two treatment arms and the incidence of kidney failure (eGFR <15) nearly identical. The beneficial impact of NSS on eGFR did not result in improved survival in this study population with a median follow-up of 9.3 yr. Author contributions: Edward M. Messing had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Van Poppel, Sylvester. Acquisition of data: Van Poppel, Sylvester. Analysis and interpretation of data: Scosyrev, Messing, Sylvester, Campbell, Van Poppel. Drafting of the manuscript: Scosyrev. Critical revision of the manuscript for important intellectual content: Messing, Sylvester, Campbell, Van Poppel. Statistical analysis: Scosyrev, Sylvester. Obtaining funding: Van Poppel, Sylvester. Administrative, technical, or material support: None. Supervision: Van Poppel, Sylvester. Other (specify): None. Financial disclosures: Edward M. Messing certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None. Funding/Support and role of the sponsor: This study was supported by Fond Cancer (FOCA) in Belgium. The funding source had no role in the design, conduct, or analysis of this study, interpretation of the data, writing of this paper, or decision to submit it for publication.
Appendix – Analysis of lowest estimated glomerular filtration rate by assigned treatment, with stratification on baseline renal function and chronic disease Outcome BSC 1.25 ULN
BSC >1.25 ULN
No chronic disease
eGFR eGFR eGFR eGFR eGFR eGFR eGFR eGFR eGFR eGFR eGFR eGFR
<60 <45 <30 <15 <60 <45 <30 <15 <60 <45 <30 <15
RN
NSS
p*
207/242 (85.5) 118/242 (48.8) 22/242 (9.1) 4/242 (1.7) 15/17 (88.2) 9/17 (52.9) 4/17 (23.5) 0/17 (0.0) 142/166 (85.5) 71/166 (42.8) 11/166 (6.6) 1/166 (0.6)
151/237 (63.7) 60/237 (25.3) 13/237 (5.5) 3/237 (1.3) 14/17 (82.4) 9/17 (52.9) 3/17 (17.7) 1/17 (5.9) 97/162 (59.9) 39/162 (24.1) 4/162 (2.5) 0/162 (0.0)
<0.001
0.25
<0.001
Please cite this article in press as: Scosyrev E, et al. Renal Function After Nephron-sparing Surgery Versus Radical Nephrectomy: Results from EORTC Randomized Trial 30904. Eur Urol (2013), http://dx.doi.org/10.1016/j.eururo.2013.06.044
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Appendix (Continued ) Outcome Chronic disease
eGFR eGFR eGFR eGFR
<60 <45 <30 <15
nephrectomy for low-stage renal cell carcinoma. Eur Urol 2007; RN
80/93 56/93 15/93 3/93
(86.0) (60.2) (16.1) (3.2)
NSS 68/93 30/93 12/93 4/93
(73.1) (32.3) (12.9) (4.3)
p* 0.003
51:1606–15. [4] Levey AS, Greene T, Kusek J, Beck G. A simplified equation to predict glomerular filtration rate from serum creatinine [abstract]. J Am Soc Nephrol 2000;11:155A. [5] Levey AS, Coresh J, Greene T, et al. Using standardized serum creatinine values in the modification of diet in renal disease study
BSC = baseline serum creatinine; eGFR = estimated glomerular filtration rate, ml/min per 1.73 m2; NSS = nephron-sparing surgery; RN = radical nephrectomy; ULN = upper limit of normal. Data are presented as counts with percentages in parentheses. * Wilcoxon-Mann-Whitney test.
equation for estimating glomerular filtration rate. Ann Intern Med 2006;145:247–54. [6] Levey AS, de Jong PE, Coresh J, et al. The definition, classification, and prognosis of chronic kidney disease: a KDIGO Controversies Conference report. Kidney Int 2011;80:17–28. [7] Desu MM, Raghavarao D. Nonparametric statistical methods for
References
complete and censored data. Boca-Raton, FL: Chapman & Hall/CRC; 2004.
[1] Kim SP, Thompson RH, Boorjian SA, et al. Comparative effectiveness
[8] Go AS, Chertow GM, Fan D, et al. Chronic kidney disease and the
for survival and renal function of partial and radical nephrectomy
risks of death, cardiovascular events, and hospitalization. N Engl J
for localized renal tumors: a systematic review and meta-analysis. J Urol 2012;188:51–7. [2] Van Poppel H, Da Pozzo L, Albrecht W, et al. A prospective randomized EORTC intergroup phase 3 study comparing the oncologic
Med 2004;351:1296–305. [9] Stevens LA, Coresh J, Greene T, Levey AS. Assessing kidney function— measured and estimated glomerular filtration rate. N Engl J Med 2006;354:2473–83.
outcome of elective nephron-sparing surgery and radical nephrec-
[10] Lane BR, Campbell SC, Demirjian S, Fergany AF. Surgically-induced
tomy for low-stage renal cell carcinoma. Eur Urol 2011;59:
chronic kidney disease may be associated with lesser risk of pro-
543–52.
gression and mortality than medical chronic kidney disease. J Urol
[3] Van Poppel H, Da Pozzo L, Albrecht W, et al. A prospective randomized EORTC intergroup phase 3 study comparing the complications of elective nephron-sparing surgery and radical
2013;189:1649–55. [11] Ibrahim HN, Foley R, Tan L, et al. Long-term consequences of kidney donation. N Engl J Med 2009;360:459–69.
Please cite this article in press as: Scosyrev E, et al. Renal Function After Nephron-sparing Surgery Versus Radical Nephrectomy: Results from EORTC Randomized Trial 30904. Eur Urol (2013), http://dx.doi.org/10.1016/j.eururo.2013.06.044