Baseline Glomerular Filtration Rate and Cisplatin- Induced Renal Toxicity in Urothelial Cancer Patients

Abstract

Cisplatin’s nephrotoxicity limits its use in patients with renal insufficiency. In our study of 81 urothelial cancer patients treated with cisplatin, those with glomerular filtration rate (GFR) < 60 mL/min did not experience a greater decline in renal function compared to patients with GFR ≥ 60 mL/min. These findings may support extending the option of cisplatin-based therapy to previously ineligible patients.

Background:

Cisplatin eligibility for clinical trials has been defined as glomerular filtration rate (GFR) ≥ 60 mL/min due to the risk of nephrotoxicity in patients with renal impairment. For urothelial cancer, substitution of carboplatin instead of cisplatin compromises outcomes. We evaluated change in GFR in patients treated with cisplatin despite baseline GFR < 60 mL/min to determine risk of nephrotoxicity.

Patients and Methods:

Patients treated between 2009 and 2014 at our institution were identified by the institutional review board—approved cystectomy database. GFR percentage change was compared by age (< 75 vs. ≥ 75 years), pretreatment GFR (< 60 vs. ≥ 60 mL/min), therapy setting (neoadjuvant, adjuvant, or metastatic), primary disease site, and comorbidities (diabetes, hypertension, and hyperlipidemia). The associations between overall survival and age or GFR were also assessed.

Results:

There were 81 patients who received cisplatin-based therapy and whose pre- and posttreatment GFR were available. Median GFR change was −1.6% for patients with pretreatment GFR < 60 mL/min compared to −10.9% for patients with pretreatment GFR ≥ 60 mL/min (P = .17). Therapy setting was the only factor in our study to be significantly associated with GFR change (P = .027). No association was found between overall survival and pre- or posttreatment GFR, GFR percentage change, or age.

Conclusion:

Our data support the hypothesis that urothelial cancer patients with GFR < 60 mL/min do not experience a greater decline in renal function after cisplatin compared to patients with GFR ≥ 60 mL/min. If validated, this may extend the option of cisplatin-based therapy to previously ineligible patients.

Introduction

There are an estimated 79,000 new diagnoses of urothelial cancer and over 16,000 deaths due to urothelial cancer in the United States each year.¹ Combination cisplatin-based chemotherapy with either gemcitabine plus cisplatin (GC) or methotrexate, vinblastine, and doxorubicin plus cisplatin (MVAC) is the standard of care for metastatic patients, inducing significant responses and even a small percentage of durable remissions.² Treatment is further complicated by the fact that urothelial cancer patients are often elderly and have comorbidities. The influence of these factors on patterns of care and treatment outcomes has not been well described.

Because of comorbidities and frequent presentation with urinary outflow obstruction, renal insufficiency is common in urothelial cancer patients. Approximately 30% to 50% of urothelial cancer patients are ineligible for standard cisplatin-based chemotherapy.³ Recent consensus has defined cisplatin eligibility as calculated creatinine clearance or glomerular filtration rate (GFR) of ≥ 60 mL/ min as a result of the greater risk of renal and other toxicities in patients with renal impairment treated with cisplatin.⁴ Although different methods for determining GFR result in different values, thus affecting whether a patient is classified as eligible for cisplatin or not, the Cockcroft-Gault equation remains one of the most common tools used by practicing oncologists to characterize a patient’s renal function, despite its tendency to underestimate GFR.⁵ Because cisplatin is considered superior to carboplatin for urothelial cancer patients,⁶ patients with renal impairment may be denied treatment with MVAC and GC, and thus potential long-term remission.

The Urology Institute and the Keck School of Medicine of the University of Southern California (USC) has an internationally recognized urologic oncology program with a particular focus on urothelial cancer. Given the large number of advanced urothelial cancer patients treated at our institution, as well as our institution’s flexible cutoff of GFR for cisplatin eligibility, we reviewed our experience with patients who received cisplatin-based chemotherapy despite a GFR of < 60 mL/min to determine whether they experienced a greater rate of renal function deterioration. This includes a population of patients treated with modified regimens, such as split-dose cisplatin, which has been postulated to reduce renal toxicity.⁷ Additionally, we investigated whether there was excess hematologic toxicity in patients with renal impairment, and we also assessed the cohort’s overall survival (OS). Subjective toxicities such as neuropathy and ototoxicity could not be assessed because of the limitations of the retrospective study design. Our aim was to determine whether a more liberal definition of GFR for cisplatin eligibility could be considered.

Patients and Methods

Patients who received systemic therapy for urothelial cancer from January 2009 to December 2014 at USC were identified by the institutional review board—approved cystectomy database, which includes upper tract urothelial cancer cases. We focused on the first cisplatin-based therapy the patients received in the neoadjuvant, adjuvant, or metastatic setting.

Creatinine and weight values closest to start and end dates of cisplatin-based therapy were used for the calculation of GFR using the Cockcroft-Gault formula. All patients received 0.9% saline hydration before and after cisplatin treatment, which is uniformly practiced at our institution. Cisplatin infusion rates ranged from 1 to 2 hours, and routine use of diuretics or nephroprotective agents is not practiced at our institution. Standardized antiemetic prophylaxis included granisetron, aprepitant, and dexamethasone.

The posttreatment GFR was calculated using the serum creatinine and weight level temporally closest to the end of the final chemotherapy cycle, regardless of whether this was higher or lower than previous or subsequent values. Posttreatment GFR was compared to pretreatment GFR for each patient, and the percentage change in GFR from baseline values was calculated. Wilcoxon rank-sum test and analysis of variance (ANOVA) were used to assess whether there was a significant difference in GFR percentage change by age, pretreatment GFR, therapy setting (neoadjuvant, adjuvant, or metastatic), primary disease site (bladder vs. upper tract), or comorbidities (diabetes, hypertension, and hyperlipidemia) that might contribute to underlying medical renal disease. Because there were some large values in GFR percentage changes, ANOVA was performed on the ranks of GFR percentage change values.

Log-rank tests were used to examine whether there was a significant association between OS and age, pre- and posttreatment GFR, GFR percentage change, or number of chemotherapy cycles. OS was defined as the duration in time from the end of the first cisplatin-based therapy to death. Patients who were alive were censored at their last follow-up date. Analyses on OS were performed separately for the neoadjuvant, adjuvant, and metastatic settings. For each setting, 2-year and 5-year OS rates based on the Kaplan-Meier method with Greenwood standard errors are presented for all patients, then by pre- and posttreatment GFR, GFR percentage change, age, or number of chemotherapy cycles. Exploratory analyses on the associations between these variables and OS were also performed with univariate Cox regression models (Supplemental Table 1 in the online version). Given the small sample size, multivariable analyses had low statistical power and were not performed. All P values reported are 2 sided. P ≤ .05 was considered statistically significant.

Statistical analyses were performed by Stata 11.0 (StataCorp, College Station, TX).

Results

A total of 150 patients received systemic therapy for urothelial cancer at USC from 2009 to 2014. Of those, 114 patients received at least 1 cisplatin-based therapy, and the other 36 were excluded because they received of non—cisplatin-based therapy. Of the 114 patients, 93 (82%) were male and 21 (18%) were female; 29 (25%) had upper tract primary disease. Median age was 62 years (range, 31-89 years). Twenty-six received cisplatin in the neoadjuvant setting, 27 in the adjuvant setting, and 61 in the metastatic setting. More specifically, 55 of the 61 metastatic cisplatin-based therapies were provided as first-line therapy, and 6 were provided as second-line therapy or beyond. Of the 114 patients who received cisplatin-based therapy, 33 more patients were excluded as a result of lack of data for pre- and/or posttreatment creatinine and/or weight values from which to calculate GFR. This left 81 patients for analysis.

Tables 1 and 2 present the demographic characteristics and hematologic toxicities, respectively, by high (≥ 60 mL/min) and low (< 60 mL/min) baseline GFR groups. There were no significant differences between groups, except that a greater percentage of patients with GFR < 60 mL/min had upper tract disease (P = .047). There was a significant difference in the proportion of patients who received full-dose, reduced-dose, or split-dose cisplatin between patients with GFR < 60 mL/min versus patients with GFR ≥ 60 mL/min (P = .005). Full-dose cisplatin was administered to more patients with GFR ≥ 60 mL/min (50%) than patients with GFR < 60 mL/min (16%). Split-dose cisplatin was administered to 60% of patients with GFR < 60 mL/min compared to 43% with GFR ≥ 60 mL/min. Of the 26 patients who had GFR < 60 mL/min, 7 received full-dose cisplatin, though 3 subsequently had their dose reduced; 18 received split-dose cisplatin, 3 of whom had their dose reduced; and 1 was unknown. The lowest GFR in a patient receiving full-dose cisplatin was 36.7 mL/min. The lowest baseline GFR in a patient receiving any cisplatin-based regimen was 25.5 mL/min. Hematologic toxicities were not greater in patients with baseline GFR < 60 mL/min compared to those with baseline GFR ≥ 60 mL/min.

Table 1.

Demographic Characteristics According to Baseline GFR

	All Patients, N (%)	GFR < 60 mL/min, N (%)	GFR ≥ 60 mL/min, N (%)
Characteristic	(N = 81)	(N = 26)	(N = 55)	Pa
Race/Ethnicity
White	57 (70%)	18 (69%)	39 (71%)	.39
Hispanic	13 (16%)	3 (12%)	10 (18%)
Asian	6 (7%)	4 (15%)	2 (4%)
African American	1 (1%)	0 (0%)	1 (2%)
Other	4 (5%)	1 (4%)	3 (5%)
Primary Disease Site
Bladder	64 (79%)	17 (65%)	47 (85%)	.047
Renal pelvis, ureter, other	17 (21%)	9 (35%)	8 (15%)
Chemotherapy Setting
Neoadjuvant	17 (21%)	5 (19%)	12 (22%)	.99
Adjuvant	17 (21%)	6 (23%)	11 (20%)
Metastatic	47 (58%)	15 (58%)	32 (58%)
Chemotherapy Regimen
Dose-dense MVAC	15 (19%)	2 (8%)	13 (24%)	.13
GC	57 (70%)	22 (84%)	35 (64%)
Other	9 (11%)	2 (8%)	7 (13%)
No. of Chemotherapy Cycles
1-3	14 (17%)	4 (15%)	10 (18%)	.39
4	47 (58%)	18 (69%)	29 (53%)
>4	20 (25%)	4 (15%)	16 (29%)
Cisplatin Administration
Full dose	31 (39%)	4 (16%)	27 (50%)	.005
Reduced dose	10 (13%)	6 (24%)	4 (8%)
Split dose	38 (48%)	15 (60%)	23 (43%)
Unknown	2	1	1
Comorbidity
Hypertension	35 (43%)	15 (58%)	20 (36%)	.094
Diabetes mellitus	10 (12%)	4 (15%)	6 (11%)	.72
Hyperlipidemia	19 (23%)	11 (42%)	8 (15%)	.010

Abbreviations: GC = gemcitabine and cisplatin; GFR = glomerular filtration rate; MVAC = methotrexate, vinblastine, doxorubicin, and cisplatin.

^aFisher’s exact tests. Patients with unknown values were excluded from analysis.

Table 2.

Hematologic Toxicities According to Baseline GFR

Toxicity	Total, N (%)	GFR < 60 mL/min, N (%)	GFR ≥ 60 mL/min, N (%)	Pa
Lowest ANC (per μL)
≥1000	38 (51%)	11 (44%)	27 (55%)	.59
<1000	17 (23%)	6 (24%)	11 (22%)
<500	19 (26%)	8 (32%)	11 (22%)
Unknown	7	1	6
Lowest Platelet Count (per μL)
≥50,000	64 (83%)	21 (84%)	43 (83%)	.39
<50,000	7 (9%)	1 (4%)	6 (12%)
<25,000	6 (8%)	3 (12%)	3 (6%)
Unknown	4	1	3
Lowest Hemoglobin (g/dL)
≥8	64 (83%)	19 (76%)	45 (87%)	.29
<8	12 (16%)	6 (24%)	6 (12%)
<6.5	1 (1%)	0	1 (2%)
Unknown	4	1	3

Abbreviations: ANC = absolute neutrophil count; GFR = glomerular filtration rate.

^aFisher’s exact test. Patients with unknown values were excluded from analysis.

Figure 1 depicts scatterplots of patients’ GFR percentage change versus pretreatment GFR and patients’ pre- versus posttreatment GFR. Median GFR change was −1.6% (range, −50% to +49%) for patients with pretreatment GFR < 60 mL/min, compared to −10.9% (range, −72% to +135%) for patients with pretreatment GFR ≥ 60 mL/min (P = .17). Therapy setting (neoadjuvant, adjuvant, or metastatic) had significant association with GFR change (P = .027) and was the only factor in our study to be associated with GFR percentage change, with metastatic patients experiencing a greater change. Median GFR changes for the neoadjuvant setting, adjuvant setting and metastatic setting were 5% (range, −32% to +90%), −6% (range, −39% to +20%), and −12% (range, −72% to +135%), respectively.

Figure 1.

Scatterplots of GFR Percentage Change Versus Pretreatment GFR (Left) and Pre- Versus Posttreatment GFR (Right)

Abbreviation: GFR = glomerular filtration rate.

Figure 2 depicts the distribution of GFR percentage change by age at start of cisplatin treatment, pretreatment GFR, primary disease site, and comorbidities including diabetes mellitus, hypertension, and hyperlipidemia. Only hypertension was significantly associated with GFR percentage change at the .05 significance level. Patients without hypertension experienced a larger GFR drop compared to patients with hypertension (P = .030), but this was not significant after controlling for GFR at the start of therapy (P = .076).

Figure 2.

Distribution of GFR Percentage Change by Age at Start of Cisplatin Therapy, Pretreatment GFR, Primary Disease Site, and Comorbidities

Abbreviation: GFR = glomerular filtration rate.

Table 3 presents the results of log-rank tests examining the OS rates at 2 and 5 years after completion of cisplatin therapy in the neoadjuvant, adjuvant, and metastatic settings. Univariate analysis did not show an association between OS and pretreatment GFR, posttreatment GFR, GFR percentage change, age at start of treatment, primary disease site (upper tract vs. bladder), and type of regimen (dose-dense MVAC vs. GC) in any of the cohorts stratified by therapy setting (metastatic vs. perioperative).

Table 3.

Overall Survival Rates (± Standard Error) at 2 and 5 Years by Pre- and Posttreatment GFR, GFR Percentage Change, Number of Chemotherapy Cycles, and Age

	Neoadjuvant				Adjuvant				Metastatic
Cohort	N	2 Years	5 Years	Pa	N	2 Years	5 Years	Pa	N	2 Years	5 Years	Pa
All patients	17	57 ± 13%	21 ± 17%		17	94 ± 6%	56 ± 24%		47	56 ± 10%	37 ± 13%
Pretreatment GFR
<60 mL/min	5	50 ± 25%	NA	.55	6	100%	NA	.35	15	51 ± 15%	51 ± 15%	.36
≥60 mL/min	12	61 ± 15%	23 ± 18%		11	90 ± 9%	51 ± 23%		32	58 ± 13%	29 ± 16%
Posttreatment GFR
<60 mL/min	4	50 ± 25%	NA	.37	6	100%	0%	.96	20	64 ± 14%	64 ± 14%	.52
≥60 mL/min	13	60 ± 15%	23 ± 18%		11	90 ± 9%	75 ± 16%		27	51 ± 13%	NA
GFR Percentage Change
Less than 25% decrease	1	NA	NA	.10	4	100%	0%	.36	13	80 ± 13%	40 ± 29%	.37
More than 25% decrease	6	33 ± 19%	NA		7	100%	100%		19	43 ± 20%	21 ± 18%
Increase	10	75 ± 15%	25 ± 21%		6	83 ± 15%	NA		15	49 ± 16%	NA
No. of Chemotherapy Cycles
1-3	3	100%	100%	.062	1	100%	0%	.42	10	NA	NA	.003
4	14	45 ± 16%	0%		15	93 ± 6%	82 ± 12%		18	47 ± 14%	35 ± 15%
>4	0				1	NA	NA		19	85 ± 10%	42 ± 30%
Age at Start of Treatment
<75 years	15	51 ± 14%	19 ± 16%	.29	14	92 ± 7%	53 ± 23%	.47	36	59 ± 12%	36 ± 18%	.30
≥75 years	2	100%	NA		3	100%	NA		11	45 ± 18%	NA

Abbreviations: GFR = glomerular filtration rate; NA = not available (follow-up data not available).

^aLog-rank test.

Figures 3 and 4 depict the OS curves for patients who received cisplatin-based therapy in the metastatic setting. Of the 47 patients who received cisplatin in the metastatic setting, 42 received the therapy as first-line therapy, and 5 received it as second-line therapy or beyond.

Figure 3.

Overall Survival by Pretreatment GFR (Top Left), Posttreatment GFR (Top Right), GFR Percentage Change (Bottom Left), and Age at Start of Cisplatin Therapy (Bottom Right) for Patients Treated in Metastatic Setting

Abbreviation: GFR = glomerular filtration rate.

Figure 4.

Overall Survival by Number of Chemotherapy Cycles for Patients Treated in Metastatic Setting

Discussion

Combination cisplatin-based chemotherapy in the form of MVAC, dose-dense MVAC, GC, and dose-dense GC is the standard of care for patients with advanced urothelial cancer because of the potential for long-term survival even in a subset of metastatic patients.^2,8 However, nephrotoxicity limits the use of cisplatin in patients with decreased renal function, a common comorbidity in patients with urothelial tract cancers. Cisplatin is cleared by the kidney and actively accumulates in renal parenchymal cells, causing damage to nuclear and mitochondrial DNA and leading to apoptosis and necrosis in the kidney.⁹ Nephrotoxicity increases with the dose, infusion rate, and cumulative dose of cisplatin.⁹ Aggressive hydration with 0.9% saline has been the primary means of preventing nephrotoxicity during cisplatin administration. Reduced-dose or split-dose cisplatin, as well as slower infusion rates, may prevent toxicity by reducing the rate of cisplatin being cleared by the kidney at any given point in time.¹⁰ Limited prospective data exist for these modifications, but one study of 23 patients with muscle-invasive bladder cancer treated with split-dose cisplatin with gemcitabine in the neoadjuvant setting found good efficacy, with 11 of 23 having a pathologic complete response; however, interpretation is complicated because 9 of the 11 received radiation.¹¹

Recent consensus has defined cisplatin eligibility as calculated creatinine clearance or GFR of ≥ 60 mL/min as a result of the concern for a greater risk of renal and other toxicities in patients with renal impairment treated with cisplatin.⁴ In patients ineligible for cisplatin-based therapy, carboplatin-based regimens, such as gemcitabine/carboplatin or methotrexate, carboplatin, and vinblastine, are acceptable but are likely inferior first-line options.¹² In a meta-analysis comparing carboplatin-based regimens and cisplatin-based regimens in urothelial cancer, carboplatin-based regimens had a lower likelihood of achieving complete response and lower overall response.⁶ Because patients with lower GFR are excluded from cisplatin-based clinical trials, retrospective data provide an important starting point to test the hypothesis that cisplatin can be safely administered to patients with lower GFR. Our data set identified no significant change in renal function or greater likelihood of hematologic toxicities in patients who received cisplatin-based chemotherapy despite a GFR < 60 mL/min. These data fit with the Cleveland Clinic experience, in which 17 bladder cancer patients with GFR < 60 mL/min were found to have a similar rate of renal toxicity during neoadjuvant cisplatin chemotherapy compared to 74 with GFR ≥ 60 mL/min.¹³ Together, these experiences support prospective testing of a lower GFR entry criterion in future trials to potentially extend the more effective option of cisplatin to patients previously deemed ineligible for this therapy.

In the population studied, cisplatin was safely administered to patients with GFR < 60 mL/min, and even to patients with very low GFR; the lowest GFR in our series was 25.5 mL/min calculated by the Cockcroft-Gault formula. Comparing patients with pretreatment GFR ≥ 60 mL/min and those with pretreatment GFR < 60 mL/min, there was no significant difference in GFR percentage change after cisplatin therapy. Compared to patients with pretreatment GFR ≥ 60 mL/min, a greater percentages of those with pretreatment GFR < 60 mL/min received split-dose or reduced-dose cisplatin. Importantly, the reference standard method of measuring GFR, the 24-hour urine collection, was not performed in the study population, and thus GFR levels could have been better than what was calculated. Future studies should include the Modification of Diet in Renal Disease Study equation and/or 24-hour urine measurement. We would not recommend administration of cisplatin-based chemotherapy to patients with GFR < 45 mL/min outside of a clinical trial, and we recommend using 24-hour urine collection in patients with borderline calculated GFR to better determine actual renal function.

Urothelial cancer patients tend to be elderly with comorbid diseases such as diabetes mellitus, hypertension, and hyperlipidemia that contribute to renal impairment. We hypothesized that these medical reasons for renal insufficiency might indicate kidneys that were more at risk for GFR decline after cisplatin administration. However, there was no difference in risk of GFR decline based on these comorbidities. Obstructive nephropathy is another common cause of low GFR, particularly in urothelial cancer patients as a result of tumor location. Percutaneous nephrostomy to alleviate obstruction followed by monitoring for improvement in GFR is important in evaluating eligibility for cisplatin in this population.

Univariate analysis of the neoadjuvant, adjuvant, and metastatic cohorts did not show a statistically significant association between OS and pretreatment GFR, posttreatment GFR, GFR percentage change, and age at start of cisplatin-based therapy. However, our analyses of OS were limited by the small sample size. With a larger sample size, additional cutoffs for GFR could be explored, such as 50 to 59 mL/min and 40 to 49 mL/min. In addition, there is potential bias in the way patients were selected for cisplatin despite low GFR. Future studies should include Eastern Cooperative Oncology Group performance status, as this could influence dose reductions or delays and number of cycles administered. This study could not address the survival or disease control impact of providing cisplatin-based therapy to patients with low GFR. In the future, the neoadjuvant setting presents an opportunity to evaluate efficacy signal by using a benchmark of response that uses pathologic complete response. This would provide a more rapid assessment than relapse-free survival or OS, though these remain the end points of greatest clinical interest for patients in the perioperative setting.

The retrospective nature of our study also limits our ability to assess subjective toxicities of interest, such as neuropathy and ototoxicity, given the lack of standardized toxicity grading for patients who are not on therapeutic trials. Nevertheless, the preliminary safety data from this data set provides justification for prospective study of cisplatin-based regimens in urothelial cancer patients with low GFR. Because the majority of the low GFR patients received a modified dose (split or reduced), prospective studies should incorporate dose-modified cisplatin. Additional study would be needed to compare outcomes between modified-dose cisplatin regimens and carboplatin-based chemotherapy in this patient population. Future studies may also need to consider first-line modified cisplatin regimens compared to immunotherapy in this population.

Conclusion

Our study results do not identify greater renal dysfunction or hematologic toxicity in patients with pretreatment GFR < 60 mL/min who were treated with cisplatin. This finding challenges the current standard consensus for cisplatin eligibility and supports studies extending the option of cisplatin to previously ineligible patients, with the aim of achieving a better chance of long-term cancer-free survival. Further prospective research is needed to elucidate the relative advantage of cisplatin regimens over carboplatin regimens for patients previously considered cisplatin ineligible, as well as any increased risk of cisplatin-associated toxicities.

Clinical Practice Points.

• We found that urothelial cancer patients with pretreatment GFR < 60 mL/min do not experience a greater decline in renal function after cisplatin-based therapy compared to patients with pretreatment GFR ≥ 60 mL/min.

• Hematologic toxicities were also not greater in patients with GFR < 60 mL/min compared to those with GFR ≥ 60 mL/min.

• OS was not associated with pretreatment GFR, posttreatment GFR, GFR percentage change, or age at start of cisplatin-based therapy.

• These results suggest that a more liberal definition of GFR for cisplatin eligibility may be considered to extend the option of cisplatin-based therapy to previously ineligible patients.