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© 2003 American Society for Clinical Oncology
Estimation of the Glomerular Filtration Rate in Cancer Patients: A New Formula for New DrugsUniversity of Chicago, Chicago, IL MODERN THERAPEUTICS emphasizes regimen individualization to maximize benefit while minimizing adverse drug effects. Adjustment of a maintenance dose by interval extension, dose reduction, or a combination of both, is a commonly used strategy to avoid excess drug exposure, particularly in the presence of impaired drug elimination with renal or liver disease. In contrast to the lack of adequate markers to stratify patients with liver disease according to degrees of impairment of drug biotransformation and elimination, renal elimination of many drugs correlates closely with glomerular filtration rate (GFR). Accordingly, although dose adjustment of drugs with primarily hepatic elimination in the presence of liver disease largely remains a clinical judgment, the approach to dose adjustment of drugs with predominantly renal elimination is more quantitatively precise. It is standard practice to stratify patients in GFR ranges to guide adjusted dosing of renally eliminated drugs, and accuracy becomes particularly crucial in the drugs with low therapeutic indices.1,2 GFR-based dosing of carboplatin is fairly standard, with patients prescribed a dose designed to theoretically achieve a targeted area under the curve.3–6 Specific studies to produce guidelines for dose adjustment of renally eliminated drugs in the presence of renal impairment are increasingly required for new agents, using published guidance from the United States Food and Drug Administration (FDA)7 and other sources. In this issue of the Journal of Clinical Oncology, Takimoto et al8 report the results of a phase I and pharmacokinetic study of oxaliplatin in 37 adult cancer patients with renal impairment. This important study of the National Cancer Institute Organ Dysfunction Working Group produced data that support the authors’ recommendation that dose reduction of single-agent oxaliplatin is not necessary in patients with a calculated creatinine clearance above 20 mL per minute, as derived from demographic data and serum creatinine values using the Cockroft-Gault equation. We believe that the publication of this article provides the opportunity for a timely discussion of potential methodologic improvements to the design and analysis of drug-dosing studies in the setting of renal impairment. GFR is most accurately measured by clearance of inulin or a variety of other exogenous filtration markers, including cold iothalmate and iohexol, and hot radionuclides. These methods are not used in clinical practice. Serum creatinine values are used to define approximate cutoff levels to suggest dose reduction of some drugs, but this method is prone to a variety of errors, including the GFR-independent effects of age, sex, race, muscle mass, drugs, diet, day-to-day fluctuations, and creatinine secretion on serum creatinine concentrations.2,9 Measurement of creatinine clearance by 24-hour urine collection avoids some of these pitfalls by specifically accounting for variations in muscle mass and associated creatinine generation, but it provides an overestimate of GFR because creatinine is secreted as well as filtered. The delay for collection and analysis and the difficulties in ensuring complete urine collection are other disadvantages of this approach to GFR estimation. Numerous equations have been developed to permit GFR estimation using serum chemistries (usually serum creatinine concentration) with demographic data. The Cockroft-Gault formula is most commonly used for this purpose in adults,10 as recommended both by standard texts1,2 and by the recent FDA guidance document for dose adjustments in renal impairment.7 This formula uses serum creatinine, age, weight, and sex to estimate creatinine clearance (not actual GFR), on the basis of analysis of data collected from a group of white males in the original 1976 study, with a uniform 15% downward adjustment in women.10 Use of the lesser of lean or actual body weight is recommended for this formula. More recently, a more accurate formula for estimation of GFR (rather than creatinine clearance) was developed and validated in the analysis of the Modification of Diet in Renal Disease (MDRD) Study funded by the National Institutes of Health.11 Although mathematically complex, this formula uses readily available laboratory data (plasma creatinine [PCr, mg/dL], serum urea nitrogen [SUN, mg/dL], serum albumin [Alb, g/dL], age, sex, and race) to provide a GFR estimate more accurate than that of Cockroft-Gault or 24-hour creatinine clearance measurement, compared with the gold-standard measure, iothalmate clearance:
This formula automatically estimates body-surface area (BSA)–indexed GFR, in units of mL/min/1.73 m2, rather than estimated creatinine clearance unadjusted for BSA or race (and empirically adjusted for sex), as opposed to the results with the Cockroft-Gault equation. As in the MDRD study, measured and estimated GFR data are indexed to BSA in most recent studies funded by the National Institutes of Health or major industry of therapeutic interventions in patients with chronic kidney disease (CKD), and in selection of candidates for living kidney donation.2,9,11–13 There is a sound rationale supporting BSA indexing of GFR to avoid overdiagnosis of renal impairment in small patients and underdiagnosis of renal impairment in large individuals.14 Accordingly, a source of variability between groups in randomized studies of interventions in patients with CKD is reduced; this is an important refinement of study design because many unquantified sources of variability remain. The correlation of GFR with BSA is supported and demonstrated by a variety of experimental data.2,9,15–19 Renal and glomerular size correlate with BSA, as does metabolic rate; therefore, indexing of GFR to BSA has become standard practice. However, this approach is not without controversy.2,9,20 Although GFR adjustment to account for the effects of size and sex is appropriate, recent publications have suggested the use of approaches other than BSA indexing.20–23 Examples include indexing to height in women and in morbidly obese subjects, and to total body water in children. Although some publications have found BSA indexing unhelpful, the most rigorous study found that BSA indexing, in men and women, improved the accuracy of GFR estimation, in contrast to its failure to improve estimates of cardiac output and renal plasma flow.20 The more sophisticated technique of regression was a slight improvement compared with BSA indexing, but the demonstrated benefit was marginal. In summary, indexing of GFR to BSA is currently the best proven approach to accurate stratification of renal function. Other methods may be proven superior in the future, in some cases in selected populations, but none has replaced BSA indexing at this time. Takimoto et al8 used Cockroft-Gault–derived estimates of creatinine clearance to stratify the subjects in the oxaliplatin study. Creatinine clearance estimates were not indexed to BSA, despite the use of BSA-based dosing. In posthoc analysis, the authors report that BSA-indexing of creatinine clearance estimates did result in reclassification of several patients from one GFR range to another, but did not change the authors’ conclusions. It is conceivable that, in this study, the use of BSA-indexed GFR estimates for initial stratification would not have significantly altered results and conclusions, but this may not always be the case. However, it seems internally inconsistent to use GFR unadjusted for BSA when drug dosing is based on BSA, as in this study and in most clinical practice, however controversial the latter practice may be.24 Accordingly, we recommend that BSA indexing should be applied to adjust GFR measurements or estimates for studies of drug disposition in patients with renal impairment if dosing is based on BSA. The analysis of data from such studies should include examination of the effects of BSA-indexed and unadjusted GFR on the analysis and conclusions reached.25 We also suggest that future studies use the MDRD equation, which is superior to either Cockroft-Gault estimates or measurement by urine collection. MDRD-derived GFR estimates are readily converted to unadjusted GFR by multiplying by estimated BSA divided by 1.73 m2, so that both forms of analysis are easily performed. Accordingly, variability will be reduced by adjusting for body habitus at baseline, and the importance of this approach in stratifying dose adjustments in patients with renal impairment can be demonstrated prospectively in future oncology clinical trials. Although well proven to estimate BSA-indexed GFR in a general CKD population, it is not known whether the MDRD formula is similarly accurate in CKD patients with cancer, in whom the relationships of serum creatinine, albumin, and urea nitrogen to GFR may differ from those of the general population. It is also unproven that the use of an MDRD equation, or the use of BSA indexing of any GFR estimate, will optimize cancer chemotherapeutics in renally impaired patients, but there is a sound rationale for this approach. We recommend that future studies in these patients use the MDRD equation to stratify GFR ranges, and that data be analyzed to discern the conclusions reached from both unadjusted and BSA-indexed data with respect to the effects of GFR on drug disposition and dosing recommendations.9,25 In addition, the MDRD equation should be used to estimate GFR in the general context of oncology therapeutics, such as GFR-based dosing of carboplatin and protocol inclusion or exclusion criteria regarding the minimum acceptable GFR. REFERENCES 1. Aronoff GR, Berns JS, Brier ME, et al: Drug prescribing in renal failure: Dosing guidelines for adults (ed 4). Philadelphia, PA, American College of Physicians-American Society of Internal Medicine, 1999 2. Kasiske BL, Keane WF: Laboratory assessment of renal disease: Clearance, urinalysis, and renal biopsy, in Brenner & Rector’s The Kidney (ed 6). Philadelphia, PA, W.B. Saunders, 2000, pp 1129–1170 3. Calvert AH, Newell DR, Gumbrell LA, et al: Carboplatin dosage: Prospective evaluation of a simple formula based on renal function. J Clin Oncol 7:1748–1756, 1989[Abstract]
4. Chatelut E, Canal P, Brunner V, et al: Prediction of carboplatin clearance from standard morphological and biological patient characteristics. J Natl Cancer Inst 87:573–580, 1995 5. Dooley MJ, Poole SG, Rischin D, et al: Carboplatin dosing: Gender bias and inaccurate estimates of glomerular filtration rate. Eur J Cancer 38:44–51, 2002[Medline] 6. Calvert AH, Egorin MJ: Carboplatin dosing formulae: Gender bias and the use of creatinine-based methodologies. Eur J Cancer 38:11–16, 2002[CrossRef][Medline] 7. Drug Information Branch, Center for Drug Evaluation and Research: Guidance for Industry: Pharmacokinetics in patients with impaired renal function—Study design, data analysis, and impact on dosing and labeling, 1998. http://www.fda.gov/cder/guidance/index.htm
8. Takimoto CH, Remick SC, Sharma S, et al: A dose escalating and pharmacological study of oxaliplatin in adult cancer patients with impaired renal function: A National Cancer Institute Organ Dysfunction Group study. J Clin Oncol 21:2664–2672, 2003 9. Hsu C-Y, Chertow GM, Curhan GC: Methodological issues in studying the epidemiology of mild to moderate chronic renal insufficiency. Kidney Int 61:1567–1576, 2002[CrossRef][Medline] 10. Cockroft DW, Gault MH: Prediction of creatinine clearance from serum creatinine. Nephron 16:31–41, 1976[Medline]
11. Levey AS, Bosch JP, Breyer Lewis J, et al: A more accurate method to estimate glomerular filtration rate from serum creatinine: A new prediction equation. Ann Intern Med 130:461–470, 1999 12. Coresh J, Toto RD, Kirk KA, et al: Creatinine clearance as a measure of GFR in screenees for the African-American Study of Kidney Disease and Hypertension pilot study. Am J Kid Dis 32:32–42, 1998[Medline]
13. Parving H-H, Lehnert H, Brochner-Mortensen J, et al: The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med 345:870–878, 2001
14. Ratain MJ: Dear Doctor: We really are not sure what dose of capecitabine you should prescribe for your patient. J Clin Oncol 20:1434–1435, 2002 15. Nyengaard JR, Bendtsen TF: Glomerular number and size in relation to age, kidney weight, and body surface in normal man. Anat Rec 232:194–201, 1992[CrossRef][Medline]
16. MacKay EM: Kidney weight, body size, and renal function. Arch Intern Med 50:590–594, 1932 17. McCance RA, Widdowson EM: The correct physiological basis on which to compare infant and adult renal function. Lancet 2:860–862, 1952[Medline] 18. White AJ, Strydom WJ: Normalisation of glomerular filtration rate measurements. Eur J Nucl Med 18:385–390, 1991[CrossRef][Medline] 19. Kasiske BL, Umen AJ: The influence of age, sex, race, and body habitus on kidney weight in humans. Arch Pathol Lab Med 110:55–60, 1986[Medline] 20. Turner ST, Reilly SL: Fallacy of indexing renal and systemic hemodynamics for body surface area. Am J Physiol 268:R978–R988, 1995 21. Peters AM, Henderson BL, Lui D: Indexed glomerular filtration rate as a function of age and body size. Clin Sci (Lond) 98:439–444, 2000[Medline] 22. Anastasio P, Spirali L, Frangiosa A, et al: Glomerular filtration rate in severely overweight normotensive humans. Am J Kidney Dis 35:1144–1148, 2000[Medline] 23. Dooley MJ, Poole SG: Poor correlation between body surface area and glomerular filtration rate. Cancer Chemother Pharmacol 46:523–526, 2000[CrossRef][Medline] 24. Ratain MJ: Body-surface area as a basis for dosing of anticancer agents: Science, myth, or habit? J Clin Oncol 16:2297–2298, 1998[Medline] 25. Hsu CY, Bates DW, Kuperman GJ, et al: Relationship between hematocrit and renal function in men and women. Kidney Int 59:725–731, 2001[CrossRef][Medline]
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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