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Journal of Clinical Oncology, Vol 24, No 19 (July 1), 2006: pp. 3095-3100 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.04.3091 Formulas Calculating Creatinine Clearance Are Inadequate for Determining Eligibility for Cisplatin-Based Chemotherapy in Bladder Cancer
From the Departments of Urology and Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY Address reprint requests to Sherri Machele Donat, MD, Department of Urology, 353 E 68th St, Memorial Sloan-Kettering Cancer Center, New York, NY 10021; e-mail: donats{at}mskcc.org
PURPOSE: Efficacy of formulas calculating creatinine clearance (CrCl) to determine renal function eligibility (CrCl > 60 mL/min) for cisplatin-based chemotherapy has not been examined adequately in the bladder cancer population. We hypothesize these formulas may underestimate measured CrCl, and therefore the eligibility for cisplatin-based chemotherapy. PATIENTS AND METHODS: A database of 208 patients with unresectable or metastatic bladder cancer treated on protocol at Memorial Sloan-Kettering Cancer Center (New York, NY) with cisplatin-based chemotherapy between 1983 and 1994 was examined retrospectively. The association between measured and calculated CrCl and the ability to complete three cycles (minimum therapeutic) of chemotherapy was examined.
RESULTS: Baseline measured CrCl was less than 60 mL/min in 16% compared with 12% to 44% using various formulas. Concordance between calculated and measured CrCl less than 60 mL/min was poor (range of CONCLUSION: Current formulas estimating CrCl tend to underestimate measured CrCl, especially in those older than 65 years. Depending on the formula used, up to 44% who actually received cisplatin-based chemotherapy based on measured CrCl would be deemed ineligible at present, potentially affecting survival outcomes. Methodology for determining CrCl and/or renal eligibility for cisplatin-based chemotherapy in patients with bladder cancer should be re-examined.
A randomized Intergroup trial conducted by the Southwest Oncology Group (SWOG; SWOG 8710, INT-0080) demonstrated that the combination of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) plus radical cystectomy reduced the estimated risk of death by 25% in comparison to radical cystectomy alone.1 Meta-analyses of randomized neoadjuvant clinical trials have demonstrated improved overall survival (5% to 6.5% absolute 5-year survival) among patients with locally advanced bladder cancer receiving both radical cystectomy and cisplatin-based chemotherapy in comparison with surgery alone.2,3 Given the potential for renal toxicity with cisplatin-based chemotherapy, adequate renal function is a prerequisite, with most trials using eligibility cutoffs of a serum creatinine less than 2.0 mg/dL and/or calculated creatinine clearance (CrCl) of  60 mL/min.2-4 Substitution of cisplatin with carboplatin in MVAC regimens for patients with renal impairment resulted in inferior response and disease-specific survival rates.5 Given that treatment with cisplatin-based chemotherapy is critical for optimal survival outcomes in patients with bladder cancer, methodologies for determining CrCl and/or eligibility criteria deserve additional examination. Traditionally, CrCl has been measured using 12- or 24-hour urine collections for creatinine, or using contrast agents such as iohexol or radiolabeled agents such as chromium-51–EDTA. Coinciding with a shift to outpatient chemotherapy in the mid-1990s, mathematic formulas to estimate CrCl gained popularity; the Cockcroft-Gault and Jeliffe formulas were the two most commonly used. Most formulas used to calculate CrCl were based on younger populations and therefore may tend to underestimate the CrCl in the elderly.6,7 The accuracy of these formulas in determining renal eligibility for cisplatin-based chemotherapy has not been examined adequately in patients with bladder cancer with its elderly patient cohort (average age, 67 years in most cystectomy series).2-4 Although these formulas are convenient to use and conserve time in comparison with measured 12- and 24-hour CrCl, the trade-off in accuracy may influence patient selection for cisplatin-based chemotherapy and potentially clinical outcomes. Our hypothesis is that these formulas underestimate CrCl and therefore underestimate the eligibility for therapeutic cisplatin-based chemotherapy. To test this hypothesis, we evaluated the concordance of calculated CrCl using various published formulas with the measured CrCl in 208 patients who received combination MVAC chemotherapy for unresectable and/or metastatic bladder cancer on five protocols at Memorial Sloan-Kettering Cancer Center (MSKCC; New York, NY).
The study population consists of 208 (91%) of 229 patients treated during five MVAC trials at our institution between 1983 and 1994 for unresectable and/or metastatic urothelial cancer.8-12 Of these 229 patients, 12 patients with prior systemic chemotherapy, three patients with urothelial tumors of non–transitional cell histology, and six patients without documented measured CrCl were excluded from the analysis. The remaining 208 patients comprised our study group. All patients included in this analysis had a documented measured CrCl. Inclusion criteria for the five trials of MVAC chemotherapy studies were similar and have been published previously.8-12 All trials were approved by the institutional review board at MSKCC and informed consent was provided by all patients. Height and weight data were compiled for all patients on enrollment onto the study group. Typically, 12- or 24-hour urine specimens were submitted for measurement of CrCl after intravenous hydration in an inpatient setting and before initiation of MVAC chemotherapy. When the urine creatinine excretion seemed abnormal (or < 10 to 25 mg/kg) taking into account the patient's body weight, age, sex, and muscle mass, the urine collection was considered inadequate and urine collection was repeated.8 The renal eligibility criteria for the five trials included a serum creatinine of less than 1.7 mg/dL, blood urea nitrogen less than 30 mg/dL, and/or a measured CrCl of 40 to 60 mL/min. Patients received a median of four cycles (range, one to six cycles) of MVAC. Hydration typically was continued until blood urea nitrogen and serum creatinine returned to pretreatment levels. For the purposes of this study, we used a CrCl cutoff of 60 mL/min as a measure of renal eligibility for a cisplatin-based chemotherapy trial because it reflects current institutional practice and the trend in several recent published trials.2,3,13,14 Given that the majority of cisplatin-based chemotherapy trials, including the recently published SWOG 8710 trial for bladder cancer, use three cycles of chemotherapy as the minimum number of cycles to achieve therapeutic intent, we used the number of chemotherapy cycles completed as the end point for the ability to achieve therapeutic intent.4
Twelve previously published mathematic formulas were used to calculate CrCl (Appendix A1) for comparison to the documented measured CrCl collected for each patient. The agreement between the calculated CrCl by the formulas and the actual measured CrCl by 12- or 24-hour urinary collection was examined using three different methods. First, the relation between calculated CrCl and measured CrCl was assessed through scatter plots and Pearson correlation coefficients. Although other authors have examined the value of CrCl in a continuous scale and noted that there is bias in these estimates; the use of the cutoff is critical in deeming patients eligible for cisplatin-based chemotherapy.6,7,15 Given that the scope of our study was to assess the ability of CrCl as a binary outcome (< 60 mL/min or > 60 mL/min) to predict the ability to complete at least three cycles of chemotherapy, it was essential to use the dichotomized outcome and not CrCl in a continuous scale. Hence, we dichotomized the data based on the cutoff of 60 mL/min, and we used measures of agreement that are adequate for binary outcomes to analyze the series of 2 x 2 contingency tables. The percentages of patients deemed eligible with each formula were calculated and compared with the measured CrCl. The
Two hundred eight patients undergoing MVAC chemotherapy on protocol in a neoadjuvant, adjuvant, or metastatic setting comprised our study group (Table 1). The median age for the cohort was 61.6 years (range, 23.3 to 83.3 years), with 38% (79 of 208) of the population 65 years or older. Baseline renal function values for this cohort include a median serum creatinine of 1.1 mg/dL (range, 0.5 to 2.1 mg/dL), and a median measured CrCl of 85.8 mL/min (range, 36 to 189 mL/min). At baseline, 16% (34 of 208) of patients had a measured CrCl less than 60 mL/min. In contrast, 12% to 44% of same cohort had a calculated CrCl less than 60 mL/min, depending on the various formula used, as listed in Table 2.
The concordance between measured and calculated CrCl values less than 60 mL/min was rated poor to fair, with  values ranging from 0.14 to 0.38. Of the patients with measured CrCl less than 60 mL/min, 38% to 71% had concordant calculated CrCl less than 60 mL/min, depending on the formula used (Table 2). Conversely, of patients with a measured CrCl 60 mL/min, 7% to 39% had a discordant calculated CrCl less than 60 mL/min (Table 2). Overall correlation coefficients ranged from 0.4 to 0.6, showing moderate linear relation between all values of measured and calculated CrCl. Although the scatterplots showed a positive linear trend, they also indicated a number of patients deemed ineligible by the formulas when their measured CrCl was higher than 60 mL/min (Fig 1). For example, of the patients with a measured baseline CrCl of more than 60 mL/min, if we consider the three most commonly used formulas—the Cockroft-Gault, the Jellife 1973, and the Modified in Diet Renal Disease formulas—20%, 39%, and 22% of patients, respectively, would have had a calculated CrCl of less than 60 mL/min and most likely been declined for cisplatin-based chemotherapy at present.
Among the 79 patients older than 65, only 17 of 208 (22%) had measured CrCl less than 60 mL/min, whereas the proportion with a calculated CrCl less than 60 mL/min ranged from 11% to 56% (Table 3). Concordance between calculated CrCl less than 60 mL/min and measured CrCl less than 60 mL/min was noted in 35% to 82%, whereas 5% to 58% of patients had calculated CrCl less than 60 mL/min but measured CrCl 60 mL/min. Overall, agreement between estimated CrCl and measured CrCl is poor for elderly patients, with values from 0.14 to 0.42. Of note, the variation in percent ineligible for chemotherapy based on calculated CrCl in younger patients (age < 65) was less marked (range, 12% to 33%), with values ranging from 0.06 to 0.34 (data not shown).
Overall, 82% (170 of 208) patients in the study group received at least three cycles of cisplatin-based chemotherapy, including 68% (23 of 34) of patients with measured CrCl less than 60 mL/min and 84% (147 of 174) with measured CrCl 60 mL/min (P = .02,  2 test). Thus, patients with a measured CrCl of more than 60 mL/min were more likely to receive at least three cycles of cisplatin-based chemotherapy. In contrast, 80% to 87% of patients with calculated CrCl less than 60 mL/min and 78% to 82% of patients with calculated CrCl 60 mL/min were able to receive at least three complete cycles of chemotherapy (Table 4). There was no significant association between CrCl (< 60 versus 60 mL/min) calculated by each formula and the ability to receive at least three cycles of chemotherapy. Overall, the proportion of patients older than 65 years (82.3%; 65 of 79) versus those younger than 65 years (79%; 102 of 129) who could receive at least three cycles of MVAC chemotherapy were comparable.
Since its introduction at MSKCC, the four-drug combination of MVAC has been the standard of care in treating patients with locally advanced and metastatic transitional cell carcinoma in neoadjuvant and adjuvant settings. Recent data from a randomized study has shown similar long-term survival and less toxicity with the two-drug combination of gemcitabine and cisplatin than with MVAC9-11; however, the administration of this doublet still requires adequate renal function. The primary contemporary limitations to the use of cisplatin-based chemotherapy are the patient's baseline renal function, the migration to outpatient chemotherapy, and the inability to hospitalize patients routinely for intravenous hydration before chemotherapy.
The true proportion of patients who are deemed ineligible for cisplatin-based chemotherapy is not known.2,3,12 In the International Bladder Cancer study, 45.3% of the patients (106 of 234) with clinical stage T2-4a, Nx, M0 bladder cancer were deemed ineligible for cisplatin-based chemotherapy, including 46 with CrCl With the increasing use of mathematic formulas to calculate CrCl to determine renal eligibility for cisplatin-based chemotherapy, the ability of various formulas to accurately gauge CrCl has come under increasing scrutiny.6,7,14 Our data indicate that, regardless of the formula used, calculated CrCl correlates poorly (correlation coefficients, 0.4 to 0.6) with a CrCl measured by 12- or 24-hour urine collection (Fig 1). No one formula was found clearly to correlate better with measured CrCl and therefore no recommendations can be made in that regard. Similar findings come from an analysis of Iohexol Cooperative study, in which estimated and measured CrCl were compared in cardiac patients awaiting coronary angiography. Calculated CrCl correlated moderately (correlation coefficients, 0.53 to 0.80) with CrCl measured by concentrations of contrast agents in 24-hour urine collections.6,7,14 Our lower correlation coefficients likely represent differences in patient selection. In addition, the inaccuracies of these equations in calculating CrCl may reflect physiologic biases that influence parameters comprising the equation. For example, malnourished and ketotic patients may have a lower muscle mass, lower serum creatinine, and falsely elevated calculated CrCl. Controversies exist about calculated CrCl values in the elderly, obese, and diabetic patients, and in the setting of compromised renal function.14 With the use of calculated CrCl cutoff of 60 mL/min to determine renal eligibility for cisplatin-based chemotherapy, a significant proportion of our study cohort (12% to 44%) and the elderly subgroup (11% to 63%) would have been deemed ineligible for chemotherapy at present. By present standards, these patients either would have been given no treatment or inferior carboplatin-based regimens, and may have had worse survival outcomes.5 In our study, 7% to 39% of all study patients and 5% to 58% of the elderly subset with calculated CrCl less than 60 mL/min would have been eligible for cisplatin-based chemotherapy by evaluation of measured CrCl using the cutoff of 60 mL/min. More than 80% of all patients in our study group with calculated CrCl less than 60 mL/min (including those in the elderly subset) received at least three cycles of MVAC chemotherapy. Ineligibility based on calculated CrCls using the cutoff of 60 mL/min was not significantly associated with the ability to receive at least three cycles of chemotherapy in our cohort. Several caveats need to be examined in the interpretation of these data. Although 12- or 24-hour urine collections do not represent the gold standard for measuring CrCl, they represented the methodology for determining renal eligibility for treating patients on MVAC protocols at the time these patients received therapy. Although contrast agents such as iohexol or radiolabeled agents may provide a better method for accurately measuring CrCl, they are not cost effective or practical in the outpatient setting.14 Evaluation of the adequacy of the urine collections is limited by the retrospective nature of this study; however, the CrCl values reported here were measured under supervision during hospitalization, and patients received intensive hydration before chemotherapy to increase urinary outputs to 100 mL/h or more during chemotherapy administration. MVAC toxicity was minimized in patients with marginal measured CrCl by cisplatin dose adjustments and mannitol hydration, which is not as easily done in the current outpatient setting of chemotherapeutic administration.15 Even with these precautions, there were six treatment-related deaths in these patients.16,17 Of these six treatment-related deaths, only one patient had measured CrCl less than 60 mL/min: formulas also identified the same patient with estimated CrCl less than 60 mL/min.16,17 Given that the majority of cisplatin-based chemotherapy trials, including the recently published SWOG 8710 trial for bladder cancer, use three cycles of chemotherapy as the minimum number of cycles to achieve therapeutic intent, we used the number of chemotherapy cycles completed as a surrogate end point for achieving therapeutic intent of chemotherapy.4 Although primary toxicity data may better represent tolerability of chemotherapy, these data were not available in all patients. Furthermore, although toxicity of MVAC regimens was significant, with 41% to 49% mucositis, 20% to 25% nadir sepsis, 31% to 38% renal toxicity, and 4% drug-related deaths, the majority of the renal toxicity was transient, although cumulative toxicity was noted.15,17 Finally, some of the toxicities of MVAC chemotherapy could be ascribed to the methotrexate, vinblastine, and doxorubicin. The toxicity profile associated with the current regimen of gemcitabine and cisplatin minimizes some of the febrile neutropenia, neutropenic sepsis, and mucositis seen with MVAC therapy. The proportion of bladder cancer patients with calculated CrCl less than 60 mL/min who could tolerate gemcitabine and cisplatin chemotherapy is not well known. We have shown, particularly in patients older than age 65, that formulas calculating CrCl are more likely to misclassify a patient as ineligible for cisplatin-based chemotherapy (based on a CrCl cutoff of 60 mL/min) than a measured CrCl. With the median age of 62, a significant proportion of bladder cancer patients (38%) receiving chemotherapy are older than 65 years.12 Recent studies in ovarian cancer have shown that exclusion of elderly patients from cisplatin based trials is not warranted.18 Furthermore, elderly patients with advanced urothelial cancer tolerate platinum-based chemotherapy well and derive the same benefit as their younger counterparts.19 With that in mind, the implication of our study is that the current methods of calculating CrCl by mathematic formulas is not adequate for determining renal eligibility for bladder cancer patients receiving chemotherapy, especially in patients older than 65 years. Even though measured CrCl is not the gold standard, it appears to correlate more closely with the ability to receive three cycles of cisplatin-based therapy than a calculated CrCl based on mathematic formulas in the same patient under the same treatment conditions. Therefore, the methodology used to determine renal eligibility for cisplatin chemotherapy in bladder cancer patients should be re-examined carefully in a prospective study comparing different methods of measuring and calculating CrCl, with currently used chemotherapy regimens, with a view toward minimizing toxicities and improving clinical outcomes. In the interim, it would be reasonable to return to 12- or 24-hour measured CrCl as a methodology for determining renal eligibility in patients receiving outpatient chemotherapy or as an adjunct to the calculated CrCl. Alternatively, exploration of methods allowing the delivery of a cisplatin-based chemotherapy safely to patients with renal dysfunction, such as modified cisplatin dosing regimens, is needed; there are a significant number of patients (12% to 44% in this study) who would not meet the current renal eligibility criteria of a CrCl of more than 60 mL/min.20 Finally, our data set does not allow us to redefine CrCl cutoffs accurately due to the significant differences in the overall toxicities of current therapeutic regimens (gemcitabine and cisplatin) versus those of MVAC, and the differences between inpatient chemotherapy and the outpatient setting of current chemotherapeutic administration. In conclusion, current formulas estimating CrCl by mathematic calculations tend to underestimate measured clearances, especially in those older than 65 years. Depending on the formula used, up to 44% who actually received cisplatin-based chemotherapy based on measured clearance would have been deemed ineligible for cisplatin-based chemotherapy at present, which would potentially affect survival outcomes. New methodology for determining CrCl to determine renal eligibility for cisplatin-based chemotherapy in patients with bladder cancer should be re-examined carefully with emphasis on their application to the elderly.
The authors indicated no potential conflicts of interest.
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Grossman HB, Natale RB, Tangen CM, et al: Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med 349:859-866, 2003 2. Advanced Bladder Cancer (ABC) Meta-Analysis Collaboration: Neoadjuvant chemotherapy in invasive bladder cancer: Update of a systematic review and meta-analysis of individual patient data advanced bladder cancer (ABC) meta-analysis collaboration. Eur Urol 48:202-206, 2005[CrossRef][Medline] 3. Neoadjuvant chemotherapy for invasive bladder cancer. Oxford, United Kingdom, Cochrane Library, CD005246, 18:2005 4. Pectasides D, Pectasides M, Nikolaou M: Adjuvant and neoadjuvant chemotherapy in muscle invasive bladder cancer: Literature review. Eur Urol 48:60-68, 2005[CrossRef][Medline] 5. Bellmunt J, Ribas A, Eres N, et al: Carboplatin-based versus cisplatin-based chemotherapy in the treatment of surgically incurable advanced bladder carcinoma. Cancer 80:1966-1972, 1997[CrossRef][Medline] 6. Beck CL, Pucino F, Carlson JD, et al: Evaluation of creatinine clearance estimation in an elderly male population. Pharmacotherapy 8:183-188, 1988[Medline] 7. Malmrose LC, Gray SL, Pieper CF, et al: Measured versus estimated creatinine clearance in a high-functioning elderly sample: MacArthur Foundation Study of Successful Aging. J Am Geriatr Soc 41:715-721, 1993[Medline] 8. Markantonis S, Agathokleous-Kioupaki E: Can two-, four- or eight-hour urine collections after voluntary voiding be used instead of twenty-four-hour collections for the estimation of creatinine clearance in healthy subjects? Pharm World Sci 20:258-263, 1998[CrossRef][Medline] 9. von der Maase H: Current and future perspectives in advanced bladder cancer: Is there a new standard? Semin Oncol 29:3-14, 2002[Medline] 10. von der Maase H, Hansen SW, Roberts JT, et al: Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: Results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol 18:3068-3077, 2000 11. von der Maase H, Sengelov L, Roberts JT, et al: Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. J Clin Oncol 23:4602-4608, 2005 12. Advanced Bladder Cancer (ABC) Meta-Analysis Collaboration: Adjuvant chemotherapy in invasive bladder cancer: A systematic review and meta-analysis of individual patient data Advanced Bladder Cancer (ABC) Meta-analysis Collaboration. Eur Urol 48:189-201, 2005[CrossRef][Medline] 13. Fossa SD, Skovlund E: Selection of patients may limit the generalizability of results from cancer trials. Acta Oncol 41:131-137, 2002[CrossRef][Medline] 14. Spinler SA, Nawarskas JJ, Boyce EG, et al: Predictive performance of ten equations for estimating creatinine clearance in cardiac patients. Iohexol Cooperative Study Group. Ann Pharmacother 32:1275-1283, 1998[Abstract] 15. Sternberg CN, Yagoda A, Scher HI, et al: M-VAC (methotrexate, vinblastine, doxorubicin and cisplatin) for advanced transitional cell carcinoma of the urothelium. J Urol 139:461-469, 1988[Medline] 16. Bajorin DF, Dodd PM, Mazumdar M, et al: Long-term survival in metastatic transitional-cell carcinoma and prognostic factors predicting outcome of therapy. J Clin Oncol 17:3173-3181, 1999 17. Sternberg CN, Yagoda A, Scher HI, et al: Methotrexate, vinblastine, doxorubicin, and cisplatin for advanced transitional cell carcinoma of the urothelium: Efficacy and patterns of response and relapse. Cancer 64:2448-2458, 1989[CrossRef][Medline] 18. Hershman D, Jacobson JS, McBride R, et al: Effectiveness of platinum-based chemotherapy among elderly patients with advanced ovarian cancer. Gynecol Oncol 94:540-549, 2004[CrossRef][Medline] 19. Bamias A, Efstathiou E, Moulopoulos LA, et al: The outcome of elderly patients with advanced urothelial carcinoma after platinum-based combination chemotherapy. Ann Oncol 16:307-313, 2005 20. Hussain SA, Stocken DD, Riley P, et al: A phase I/II study of gemcitabine and fractionated cisplatin in an outpatient setting using a 21-day schedule in patients with advanced and metastatic bladder cancer. Br J Cancer 91:844-849, 2004[Medline] Submitted September 19, 2005; accepted April 14, 2006.
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
50 mL/min calculated by the Cockcroft-Gault equation.
