Nephrology

At the American Society of Nephrology Renal Week 2010, one of the authors (A.D.R.) presented the following question at an In-Depth Nephrology Course on Geriatric Nephrology:

See related article

A 65-year-old woman donated a kidney to her son. Before donation, her serum creatinine level was 1.0 mg/dL, her estimated glomerular filtration rate (GFR) was 56 mL/min/1.73 m², and her measured GFR was 82 mL/min/1.73 m², which was below the 2.5th percentile for 20-year-old potential kidney donors. The patient had no albuminuria or hypertension and was otherwise healthy. The kidney was biopsied during the transplant surgery. The biopsy revealed 2 of 20 glomeruli as globally sclerosed, a focus of tubular atrophy, and mild arteriosclerosis (findings present in less than 2.5% of 20-year-old donors).

Choose one. Prior to donation, this woman had:

• Chronic kidney disease (CKD), and she should not have donated her kidney
• CKD, but kidney donation was reasonable
• Age-related (senescent) changes in her kidneys, and should not have donated her kidney
• Age-related (senescent) changes in her kidneys, but kidney donation was reasonable

Using an electronic response system, 36 (82%) of 44 physicians in the audience chose the last option, even though this patient meets the current definition of CKD (an estimated GFR less than 60 mL/min/1.73 m²) and has chronic parenchymal damage documented by a kidney biopsy.

PROBLEMS WITH THE GFR AND CKD CLASSIFICATION

This question highlights several key problems with the GFR and CKD classification.

First, in low-risk populations such as potential kidney donors, serum-creatinine-based equations such as the Modification of Diet in Renal Disease (MDRD) equation and the Chronic Kidney Disease Epidemiology Study (CKD-EPI) equation substantially underestimate the GFR.¹

Second, many healthy older adults with normal serum creatinine levels have an estimated GFR and a measured GFR below the normal range for young adults.²

Third, many healthy older adults have evidence of chronic parenchymal damage on renal biopsy, unlike healthy young adults.³

Finally, many health care providers did not previously recognize that people with a normal serum creatinine level could have a reduced GFR, and widespread use of the estimated GFR has addressed this problem. However, many physicians remain skeptical about efforts this past decade to classify age-related changes in kidney function as a “disease” in the absence of a clear benefit to older patients.⁴

TWO POINTS ABOUT THE ESTIMATED GFR

In this issue of the Cleveland Clinic Journal of Medicine, Simon and colleagues⁵ provide a balanced assessment of the benefits and pitfalls of using the estimated GFR in clinical practice. Two points they make deserve further discussion:

Bigger people make more creatinine. GFR can be reported in units of milliliters per minute, or in units normalized to body surface area (mL/min/1.73 m²). Contemporary equations for identifying and classifying CKD use the latter, because the GFR is considered inappropriately low when metabolic waste is not being adequately cleared. It is intuitive that smaller people require less absolute GFR than larger people, who generate more metabolic waste. Indexing GFR to 1.73 m² assumes that body surface area is a good surrogate for metabolic waste generation. However, whether body surface area is the best surrogate for the rate of metabolic waste generation has long been a subject of debate.⁶

The relationship between GFR and serum creatinine is not linear. Due to the inverse relationship between serum creatinine and GFR, a small change in serum creatinine from 0.9 to 1.2 mg/dL will represent a relatively large change in GFR (eg, 85 to 65 mL/min/1.73 m²), whereas a large change in serum creatinine from 5 to 9 mg/dL will represent a smaller change in GFR (eg, 10 to 5 mL/min/1.73 m²). The latter may be of great concern since it represents a fall in GFR to levels at which dialysis is likely needed. With the former, subtle changes in serum creatinine represent large changes in GFR, but there is also much more day-to-day variability in GFR in the normal or near-normal range than in the advanced range of kidney disease. This is one of the reasons the MDRD and CKD-EPI equations were developed, using logarithmic models that emphasize percentage instead of absolute differences in GFR.

BEYOND CREATININE?

As Simon and colleagues point out,⁵ although serum creatinine is a flawed surrogate for GFR, there are many problems with determining GFR by other means.

Direct GFR measurement relies on the use of an exogenous marker such as inulin or iothalamate that is infused or injected, followed by timed urine and plasma measurements to calculate GFR by the urinary clearance method (UV/P, where U is the concentration of the marker in the urine, V is the urine volume, and P is the concentration of the marker in the plasma). Alternatively, timed plasma measurements of the marker alone can be used to determine GFR by the plasma clearance method. The problem is that direct GFR measurement is costly, invasive, imprecise, time-consuming, and impractical in most clinical settings.

Exogenous markers for determining GFR are chosen because they are metabolically inert, are cleared by glomerular filtration without tubular secretion or reabsorption, and have no extrarenal clearance via the liver or intestines. Endogenous markers such as serum creatinine do not fulfill all of these ideal criteria.

Simon and colleagues highlight the problem of using the estimated GFR to screen for CKD in populations of ostensibly healthy persons.⁵ The MDRD and CKD-EPI equations contain demographic variables to approximate the creatinine generation rate. The primary source of creatinine generation is muscle, and the coefficients in these equations reflect the higher muscle mass of younger individuals, males, and African Americans. However, any creatinine-based equation is fundamentally flawed because overall health also affects muscle mass: healthy people have greater muscle mass than people with chronic illness, including those with CKD. Therefore, at the same serum creatinine level, a healthy person has a higher GFR than a patient with CKD.^1,7 This problem leads to circular reasoning, since you need to know whether the patient has CKD or is healthy in order to accurately estimate GFR, but estimated GFR is being used to determine whether the patient is healthy or has CKD.

Therefore, other endogenous markers that are also eliminated via glomerular filtration, such as cystatin C, have been used to construct equations that estimate GFR. Unfortunately, factors other than GFR, such as inflammation, can also influence blood cystatin C levels. This in turn impairs the accuracy of equations that use cystatin C to estimate GFR in the general population.⁸ No known endogenous marker of GFR can be used in all patients without any confounding factors.

To rectify this problem, recent studies have investigated the use of a confirmatory test to determine which patients with a creatinine-based estimated GFR less than 60 mL/min/1.73 m² actually have kidney disease or have a false-positive result due to higher-than-average creatinine generation. Both albuminuria and elevated serum cystatin C are examples of useful confirmatory tests that substantially decrease the misdiagnosis of CKD in healthy adults with an estimated GFR less than 60 mL/min/1.73 m².^9,10

Imagine if we identified and staged systemic lupus erythematosus on the basis of antinuclear antibody levels alone: this would parallel the current approach that largely uses serum creatinine alone to classify CKD. Confirmatory tests and considering patient-specific risk factors could avoid potential harm to healthy individuals and yet retain gains that have been made to improve the interpretation of serum creatinine levels in CKD patients.

At the American Society of Nephrology Renal Week 2010, one of the authors (A.D.R.) presented the following question at an In-Depth Nephrology Course on Geriatric Nephrology:

See related article

A 65-year-old woman donated a kidney to her son. Before donation, her serum creatinine level was 1.0 mg/dL, her estimated glomerular filtration rate (GFR) was 56 mL/min/1.73 m², and her measured GFR was 82 mL/min/1.73 m², which was below the 2.5th percentile for 20-year-old potential kidney donors. The patient had no albuminuria or hypertension and was otherwise healthy. The kidney was biopsied during the transplant surgery. The biopsy revealed 2 of 20 glomeruli as globally sclerosed, a focus of tubular atrophy, and mild arteriosclerosis (findings present in less than 2.5% of 20-year-old donors).

Choose one. Prior to donation, this woman had:

• Chronic kidney disease (CKD), and she should not have donated her kidney
• CKD, but kidney donation was reasonable
• Age-related (senescent) changes in her kidneys, and should not have donated her kidney
• Age-related (senescent) changes in her kidneys, but kidney donation was reasonable

Using an electronic response system, 36 (82%) of 44 physicians in the audience chose the last option, even though this patient meets the current definition of CKD (an estimated GFR less than 60 mL/min/1.73 m²) and has chronic parenchymal damage documented by a kidney biopsy.

PROBLEMS WITH THE GFR AND CKD CLASSIFICATION

This question highlights several key problems with the GFR and CKD classification.

First, in low-risk populations such as potential kidney donors, serum-creatinine-based equations such as the Modification of Diet in Renal Disease (MDRD) equation and the Chronic Kidney Disease Epidemiology Study (CKD-EPI) equation substantially underestimate the GFR.¹

Second, many healthy older adults with normal serum creatinine levels have an estimated GFR and a measured GFR below the normal range for young adults.²

Third, many healthy older adults have evidence of chronic parenchymal damage on renal biopsy, unlike healthy young adults.³

Finally, many health care providers did not previously recognize that people with a normal serum creatinine level could have a reduced GFR, and widespread use of the estimated GFR has addressed this problem. However, many physicians remain skeptical about efforts this past decade to classify age-related changes in kidney function as a “disease” in the absence of a clear benefit to older patients.⁴

TWO POINTS ABOUT THE ESTIMATED GFR

In this issue of the Cleveland Clinic Journal of Medicine, Simon and colleagues⁵ provide a balanced assessment of the benefits and pitfalls of using the estimated GFR in clinical practice. Two points they make deserve further discussion:

Bigger people make more creatinine. GFR can be reported in units of milliliters per minute, or in units normalized to body surface area (mL/min/1.73 m²). Contemporary equations for identifying and classifying CKD use the latter, because the GFR is considered inappropriately low when metabolic waste is not being adequately cleared. It is intuitive that smaller people require less absolute GFR than larger people, who generate more metabolic waste. Indexing GFR to 1.73 m² assumes that body surface area is a good surrogate for metabolic waste generation. However, whether body surface area is the best surrogate for the rate of metabolic waste generation has long been a subject of debate.⁶

The relationship between GFR and serum creatinine is not linear. Due to the inverse relationship between serum creatinine and GFR, a small change in serum creatinine from 0.9 to 1.2 mg/dL will represent a relatively large change in GFR (eg, 85 to 65 mL/min/1.73 m²), whereas a large change in serum creatinine from 5 to 9 mg/dL will represent a smaller change in GFR (eg, 10 to 5 mL/min/1.73 m²). The latter may be of great concern since it represents a fall in GFR to levels at which dialysis is likely needed. With the former, subtle changes in serum creatinine represent large changes in GFR, but there is also much more day-to-day variability in GFR in the normal or near-normal range than in the advanced range of kidney disease. This is one of the reasons the MDRD and CKD-EPI equations were developed, using logarithmic models that emphasize percentage instead of absolute differences in GFR.

BEYOND CREATININE?

As Simon and colleagues point out,⁵ although serum creatinine is a flawed surrogate for GFR, there are many problems with determining GFR by other means.

Direct GFR measurement relies on the use of an exogenous marker such as inulin or iothalamate that is infused or injected, followed by timed urine and plasma measurements to calculate GFR by the urinary clearance method (UV/P, where U is the concentration of the marker in the urine, V is the urine volume, and P is the concentration of the marker in the plasma). Alternatively, timed plasma measurements of the marker alone can be used to determine GFR by the plasma clearance method. The problem is that direct GFR measurement is costly, invasive, imprecise, time-consuming, and impractical in most clinical settings.

Exogenous markers for determining GFR are chosen because they are metabolically inert, are cleared by glomerular filtration without tubular secretion or reabsorption, and have no extrarenal clearance via the liver or intestines. Endogenous markers such as serum creatinine do not fulfill all of these ideal criteria.

Simon and colleagues highlight the problem of using the estimated GFR to screen for CKD in populations of ostensibly healthy persons.⁵ The MDRD and CKD-EPI equations contain demographic variables to approximate the creatinine generation rate. The primary source of creatinine generation is muscle, and the coefficients in these equations reflect the higher muscle mass of younger individuals, males, and African Americans. However, any creatinine-based equation is fundamentally flawed because overall health also affects muscle mass: healthy people have greater muscle mass than people with chronic illness, including those with CKD. Therefore, at the same serum creatinine level, a healthy person has a higher GFR than a patient with CKD.^1,7 This problem leads to circular reasoning, since you need to know whether the patient has CKD or is healthy in order to accurately estimate GFR, but estimated GFR is being used to determine whether the patient is healthy or has CKD.

Therefore, other endogenous markers that are also eliminated via glomerular filtration, such as cystatin C, have been used to construct equations that estimate GFR. Unfortunately, factors other than GFR, such as inflammation, can also influence blood cystatin C levels. This in turn impairs the accuracy of equations that use cystatin C to estimate GFR in the general population.⁸ No known endogenous marker of GFR can be used in all patients without any confounding factors.

To rectify this problem, recent studies have investigated the use of a confirmatory test to determine which patients with a creatinine-based estimated GFR less than 60 mL/min/1.73 m² actually have kidney disease or have a false-positive result due to higher-than-average creatinine generation. Both albuminuria and elevated serum cystatin C are examples of useful confirmatory tests that substantially decrease the misdiagnosis of CKD in healthy adults with an estimated GFR less than 60 mL/min/1.73 m².^9,10

Imagine if we identified and staged systemic lupus erythematosus on the basis of antinuclear antibody levels alone: this would parallel the current approach that largely uses serum creatinine alone to classify CKD. Confirmatory tests and considering patient-specific risk factors could avoid potential harm to healthy individuals and yet retain gains that have been made to improve the interpretation of serum creatinine levels in CKD patients.

At the American Society of Nephrology Renal Week 2010, one of the authors (A.D.R.) presented the following question at an In-Depth Nephrology Course on Geriatric Nephrology:

See related article

A 65-year-old woman donated a kidney to her son. Before donation, her serum creatinine level was 1.0 mg/dL, her estimated glomerular filtration rate (GFR) was 56 mL/min/1.73 m², and her measured GFR was 82 mL/min/1.73 m², which was below the 2.5th percentile for 20-year-old potential kidney donors. The patient had no albuminuria or hypertension and was otherwise healthy. The kidney was biopsied during the transplant surgery. The biopsy revealed 2 of 20 glomeruli as globally sclerosed, a focus of tubular atrophy, and mild arteriosclerosis (findings present in less than 2.5% of 20-year-old donors).

Choose one. Prior to donation, this woman had:

• Chronic kidney disease (CKD), and she should not have donated her kidney
• CKD, but kidney donation was reasonable
• Age-related (senescent) changes in her kidneys, and should not have donated her kidney
• Age-related (senescent) changes in her kidneys, but kidney donation was reasonable

Using an electronic response system, 36 (82%) of 44 physicians in the audience chose the last option, even though this patient meets the current definition of CKD (an estimated GFR less than 60 mL/min/1.73 m²) and has chronic parenchymal damage documented by a kidney biopsy.

PROBLEMS WITH THE GFR AND CKD CLASSIFICATION

This question highlights several key problems with the GFR and CKD classification.

First, in low-risk populations such as potential kidney donors, serum-creatinine-based equations such as the Modification of Diet in Renal Disease (MDRD) equation and the Chronic Kidney Disease Epidemiology Study (CKD-EPI) equation substantially underestimate the GFR.¹

Second, many healthy older adults with normal serum creatinine levels have an estimated GFR and a measured GFR below the normal range for young adults.²

Third, many healthy older adults have evidence of chronic parenchymal damage on renal biopsy, unlike healthy young adults.³

Finally, many health care providers did not previously recognize that people with a normal serum creatinine level could have a reduced GFR, and widespread use of the estimated GFR has addressed this problem. However, many physicians remain skeptical about efforts this past decade to classify age-related changes in kidney function as a “disease” in the absence of a clear benefit to older patients.⁴

TWO POINTS ABOUT THE ESTIMATED GFR

In this issue of the Cleveland Clinic Journal of Medicine, Simon and colleagues⁵ provide a balanced assessment of the benefits and pitfalls of using the estimated GFR in clinical practice. Two points they make deserve further discussion:

Bigger people make more creatinine. GFR can be reported in units of milliliters per minute, or in units normalized to body surface area (mL/min/1.73 m²). Contemporary equations for identifying and classifying CKD use the latter, because the GFR is considered inappropriately low when metabolic waste is not being adequately cleared. It is intuitive that smaller people require less absolute GFR than larger people, who generate more metabolic waste. Indexing GFR to 1.73 m² assumes that body surface area is a good surrogate for metabolic waste generation. However, whether body surface area is the best surrogate for the rate of metabolic waste generation has long been a subject of debate.⁶

The relationship between GFR and serum creatinine is not linear. Due to the inverse relationship between serum creatinine and GFR, a small change in serum creatinine from 0.9 to 1.2 mg/dL will represent a relatively large change in GFR (eg, 85 to 65 mL/min/1.73 m²), whereas a large change in serum creatinine from 5 to 9 mg/dL will represent a smaller change in GFR (eg, 10 to 5 mL/min/1.73 m²). The latter may be of great concern since it represents a fall in GFR to levels at which dialysis is likely needed. With the former, subtle changes in serum creatinine represent large changes in GFR, but there is also much more day-to-day variability in GFR in the normal or near-normal range than in the advanced range of kidney disease. This is one of the reasons the MDRD and CKD-EPI equations were developed, using logarithmic models that emphasize percentage instead of absolute differences in GFR.

BEYOND CREATININE?

As Simon and colleagues point out,⁵ although serum creatinine is a flawed surrogate for GFR, there are many problems with determining GFR by other means.

Direct GFR measurement relies on the use of an exogenous marker such as inulin or iothalamate that is infused or injected, followed by timed urine and plasma measurements to calculate GFR by the urinary clearance method (UV/P, where U is the concentration of the marker in the urine, V is the urine volume, and P is the concentration of the marker in the plasma). Alternatively, timed plasma measurements of the marker alone can be used to determine GFR by the plasma clearance method. The problem is that direct GFR measurement is costly, invasive, imprecise, time-consuming, and impractical in most clinical settings.

Exogenous markers for determining GFR are chosen because they are metabolically inert, are cleared by glomerular filtration without tubular secretion or reabsorption, and have no extrarenal clearance via the liver or intestines. Endogenous markers such as serum creatinine do not fulfill all of these ideal criteria.

Simon and colleagues highlight the problem of using the estimated GFR to screen for CKD in populations of ostensibly healthy persons.⁵ The MDRD and CKD-EPI equations contain demographic variables to approximate the creatinine generation rate. The primary source of creatinine generation is muscle, and the coefficients in these equations reflect the higher muscle mass of younger individuals, males, and African Americans. However, any creatinine-based equation is fundamentally flawed because overall health also affects muscle mass: healthy people have greater muscle mass than people with chronic illness, including those with CKD. Therefore, at the same serum creatinine level, a healthy person has a higher GFR than a patient with CKD.^1,7 This problem leads to circular reasoning, since you need to know whether the patient has CKD or is healthy in order to accurately estimate GFR, but estimated GFR is being used to determine whether the patient is healthy or has CKD.

Therefore, other endogenous markers that are also eliminated via glomerular filtration, such as cystatin C, have been used to construct equations that estimate GFR. Unfortunately, factors other than GFR, such as inflammation, can also influence blood cystatin C levels. This in turn impairs the accuracy of equations that use cystatin C to estimate GFR in the general population.⁸ No known endogenous marker of GFR can be used in all patients without any confounding factors.

To rectify this problem, recent studies have investigated the use of a confirmatory test to determine which patients with a creatinine-based estimated GFR less than 60 mL/min/1.73 m² actually have kidney disease or have a false-positive result due to higher-than-average creatinine generation. Both albuminuria and elevated serum cystatin C are examples of useful confirmatory tests that substantially decrease the misdiagnosis of CKD in healthy adults with an estimated GFR less than 60 mL/min/1.73 m².^9,10

Imagine if we identified and staged systemic lupus erythematosus on the basis of antinuclear antibody levels alone: this would parallel the current approach that largely uses serum creatinine alone to classify CKD. Confirmatory tests and considering patient-specific risk factors could avoid potential harm to healthy individuals and yet retain gains that have been made to improve the interpretation of serum creatinine levels in CKD patients.

Chronic kidney disease is most often discovered and diagnosed by primary care providers. The equations for estimating the glomerular filtration rate (GFR) facilitate earlier detection of this disease. However, the estimated GFR must be interpreted in the context of the individual patient. The diagnostic criteria and staging of chronic kidney disease must be understood so that it can be recognized and managed at the earliest possible stage. In this way, primary care physicians and nephrologists can better coordinate the care of these patients.

THE STAGES OF RENAL DISEASE AND THE GFR

Before 2002, an organized approach to the clinical management of patients with renal dysfunction was hampered by a lack of a standardized way to define this condition. This changed when the National Kidney Foundation, through the Kidney Disease Outcomes Quality Initiative (K/DOQI),¹ defined the stages of chronic kidney disease based on the GFR as estimated by the Modification of Diet in Renal Disease (MDRD) equation.^2,3

See related editorial

This system has increased the recognition of chronic kidney disease by the health care community and the general public. But the entire system hinges on the utility, accuracy, and reliability of the equations used to estimate the GFR.

In this article, we review the concepts of renal clearance and how to interpret the GFR in healthy patients and in those with chronic kidney disease. The following cases illustrate the interpretation of GFR in the context of patient care.

CASE 1: A 60-YEAR-OLD WOMAN WITH A ‘NORMAL’ CREATININE LEVEL

A 60-year-old white woman with no significant medical history has routine laboratory tests done as part of her annual physical examination. She weighs 135 pounds (61.2 kg) and is 64 inches (163 cm) tall. Her serum creatinine level is 1.1 mg/dL; her estimated GFR is 53 mL/min/1.73 m². A urine dipstick test for protein and blood is normal.

CASE 2: PROTEINURIA WITH A PRESERVED GFR

A 20-year-old African American man with no medical history is undergoing routine blood testing. His serum creatinine level is 1.1 mg/dL; his estimated GFR is reported as “> 60 mL/min/1.73 m²” (calculated at 109 mL/min/1.73 m²). He is 72 inches (183 cm) tall and weighs 180 pounds (83.0 kg); he lifts weights four times a week. Urine dipstick testing reveals 3+ proteinuria.

SERUM CREATININE: AN IMPERFECT MARKER OF KIDNEY FUNCTION

Of the various functions of the kidney, the ability of the glomeruli to filter the blood, as assessed by the GFR, is considered the best index of overall kidney function.^4,5 The GFR can be thought of as the clearance of a substance from the plasma by the kidney in a period of time. This is useful because no method is available to routinely and directly measure filtration across the glomerular basement membrane.

Substances that are cleared by the kidney are used to estimate the GFR. The ideal substance for this estimate is one that is cleared only by filtration and not through metabolism or excretion by other means.

The urinary clearance of the exogenous substance inulin is considered the gold standard method, but radioisotopes such as iothalamate and other markers have replaced inulin in clinical laboratories. Because these methods are expensive, time-consuming, and not widely available, alternative methods that use endogenous markers such as creatinine have been developed for clinical practice.

The serum creatinine concentration possesses many of the qualities of an ideal marker for estimating kidney function. Creatinine is produced by the body at a relatively constant rate under normal conditions and is easy and inexpensive to measure. However, it has several limitations:

• 

  Data presented in Rolin HA III, et al. Evaluation of glomerular filtration rate and renal plasma flow. In: Jacobson HR, et al, eds. The Principles and Practice of Nephrology. St. Louis: Mosby-Year Book 1995:8-13.

  Its clearance does not solely reflect glomerular filtration because the renal tubules also excrete it into the urine.⁶ As a result, creatinine clearance (see below) will tend to overestimate the GFR (Figure 1).
• The serum creatinine concentration is directly dependent on muscle mass, which varies with sex (women tend to have less muscle mass as a percent of body weight than men), age (muscle mass decreases with age), and race (African Americans have a higher serum creatinine level for the same GFR than other Americans).⁶ Thus, there is no “normal” value for serum creatinine that applies to all patients.
• 
  Other factors can alter the creatinine level without changing the GFR, such as changes in dietary protein intake, exercise, and drugs such as cimetidine⁷ and fibrates⁸ (Table 1).

Another important point is that the relationship between the serum creatinine concentration and the GFR is parabolic.⁹ At high kidney function, large changes in the GFR are reflected by very small changes in serum creatinine—the GFR must fall quite a bit before the serum creatinine level rises very much (points A to B in Figure 1). At lower kidney function, small changes in GFR are reflected by large changes in serum creatinine (points C to D in Figure 1). This phenomenon can cause physicians to view small changes in creatinine as unimportant in patients with creatinine levels in the normal or near-normal range. Conversely, small changes may be due to random error inherent in the methods of measuring creatinine rather than to changes in kidney function.

Because the serum creatinine concentration by itself may be misleading when estimating GFR, the National Kidney Foundation and the National Kidney Disease Education Program recommend that it not be used on its own to estimate kidney function.

ESTIMATING THE GFR

Measuring 24-hour creatinine clearance

Measuring 24-hour creatinine clearance involves measuring the concentrations of creatinine in the serum and the urine and the volume of urine excreted in 24 hours.

The 24-hour creatinine clearance was long considered the best alternative to the serum creatinine concentration for assessing kidney function, as it adjusts for changes in the creatinine concentration by taking into account creatinine’s excretion in the urine. However, 24-hour urine collection is burdensome for the patient, and the results are not always reliable because of variations in collection technique. Also, using the creatinine clearance does not resolve problems with using the serum creatinine concentration, such as tubular secretion and overestimation of GFR.

In an effort to more easily estimate GFR from blood tests alone, efforts to develop mathematical equations that more closely estimate GFR began over 40 years ago. These equations take into account factors such as age, sex, and ethnicity. The best known of these are the Cockcroft and Gault¹⁰ and the MDRD equations.⁵

The Cockcroft-Gault equation

The Cockcroft-Gault equation is fairly simple, using serum creatinine, ideal body weight, and an adjustment factor for sex. Its main drawbacks are that it was developed to model creatinine clearance, itself an imperfect estimation of GFR, and it depends heavily on the accuracy of the value for “lean” body weight used in the equation.

The MDRD equation

The MDRD equation has now largely replaced the Cockcroft-Gault equation. Developed using iothalamate GFR measurements, it therefore estimates GFR rather than the less-accurate creatinine clearance. Also, it is normalized to a standard body surface area (1.73 m²), obviating the need to determine ideal body weight.

Since the estimated GFR can often be calculated using data available in most electronic medical record systems, it can be reported directly with any laboratory report that includes a serum creatinine value.

The main drawback of the MDRD equation is that it tends to underestimate GFR at higher ranges of kidney function, ie, higher than 60 mL/min/1.73 m²).^3,11

The CKD-EPI equation

The Chronic Kidney Disease Epidemiology Collaboration study (CKD-EPI) equation,¹² published in 2009, is expected to eventually replace the currently used MDRD equation, as it performs better at higher ranges of GFR.

Although the CKD-EPI equation still lacks precision and accuracy, it underestimates GFR to a lesser degree than the MDRD equation in patients with preserved renal function. Also, it was developed with the objective of reporting a specific value even when the estimated GFR is greater than 60 mL/min/1.73 m². (In contrast, when laboratories use the MDRD equation, the recommendation is to report any value above this level as “greater than 60 mL/min/1.73 m²”).

A limitation of all equations that use the serum creatinine concentration to assess kidney function is the assumption that creatinine production is both stable over time and similar among patients. As a result, these equations should not be used in situations in which renal function is changing rapidly, such as in acute kidney injury. Also, they should be used with caution in patients at the extremes of body mass, since they underestimate GFR in very muscular patients (eg, as in case 2) and overestimate GFR in very small patients (eg, as in case 1).

Calculators for estimating the GFR using these equations are available on many Web sites (see www.kidney.org/professionals/kdoqi/gfr_calculator.cfm).

SCREEN EVERYONE AT RISK

In general, anyone at higher risk of chronic kidney disease should be screened for it. This group includes US minorities and patients with hypertension, cardiovascular disease, and diabetes mellitus, among others.¹³ Screening includes an assessment of estimated GFR and urinalysis for proteinuria or hematuria.

CHRONIC KIDNEY DISEASE DEFINED: DAMAGE AND DURATION

The kidney damage can be either parenchymal renal damage independent of GFR (for example, cystic disease, glomerular hematuria, or proteinuria) or depressed GFR independent of evidence of parenchymal renal disease (an estimated GFR of less than 60 mL/min/1.73 m²).

The duration component requires that the abnormality be present for at least 3 months (ie, chronic).

 

 

Concerns about the definition

This definition has not been without controversy.

An unintended consequence of not reporting estimated GFR values above 60 mL/min/1.73 m² in absolute numbers is that providers may ignore changes in serum creatinine at estimated GFRs in this range, as they assume that the kidney function is “normal.” This may change in the future if the CKD-EPI equation is used, which produces less bias at slightly higher GFRs.

Providers may also tend to focus solely on the estimated GFR criterion and ignore other evidence of chronic kidney disease, such as abnormalities in urinalysis or imaging studies. For example, proteinuria has been shown to be more important than absolute GFR values in predicting progression of renal dysfunction and cardiovascular risk.¹⁴ Proteinuria, especially in the setting of an estimated GFR above 60 mL/min/1.73 m², can be missed if not screened for and underappreciated once found.

Moreover, in elderly patients, the current GFR equations underperform at borderline GFR values and can yield depressed values even at impressively “normal” serum creatinine levels. As a result, there is concern that chronic kidney disease is being overdiagnosed under the current system. This is especially worrisome in elderly white women without risk factors for chronic kidney disease (eg, as in case 1).

In addition, the question arises whether the arbitrary cutoff for chronic kidney disease— 60 mL/min/1.73 m²—applies to all populations.^15,16 The utility of classifying someone as having chronic kidney disease who has an estimated GFR of 55 mL/min/1.73 m² and no risk factors for chronic kidney disease (Table 2) should be questioned if the risk of progressing to end-stage renal disease or suffering a cardiovascular event is only minimally higher than in patients with a higher estimated GFR.^6,17 If the true purpose of developing the chronic kidney disease classification system is to improve patient care and outcomes, then it is of no benefit to overclassify such patients. Indeed, the stress induced by the diagnosis and the negative implications on insurance coverage and health care costs may outweigh any benefits.¹⁸

Nevertheless, these concerns do not invalidate the entire chronic kidney disease definition system, but have stimulated current efforts to improve it based on outcomes research.¹⁹

CASES REVISITED

Case 1: Problems with estimating GFR in a small woman

Case 1 has several points to note.

The patient’s small body size reflects low-level creatinine production. It is not atypical to find serum creatinine levels of 0.5 mg/dL in such patients. Thus, her serum creatinine level of 1.1 mg/dL may be abnormal. The fact that the MDRD equation “normalizes” the result to 1.73 m² of body surface area in patients with very low muscle mass will lead to an overestimation of GFR. However, she has no risk factors for chronic kidney disease.

Additionally, in up to two-thirds of patients kidney function declines with age.²⁰ Whether or not this is “normal aging” of the kidney, it is not clear that this decline in GFR reflects an underlying pathologic process.

Finally, since the patient is an older white woman, the estimated GFR tends to underestimate the true GFR. So while her body size may predispose to an overestimation of GFR, her age, race, and sex predispose to an underestimation of GFR. Many nephrologists would simply order urinalysis and ultrasonography to rule out other evidence of renal dysfunction, then recommend routine monitoring of kidney function in this case.

Case 2: Proteinuria is not normal

In case 2, because the patient is African American, young, and male, his creatinine level yields a higher estimated GFR than in case 1, despite having the same value. However, his estimated GFR still underestimates his true GFR because of his greater creatinine production due to his muscular physique.

This patient subsequently underwent iothalamate GFR testing, which yielded a GFR of 115 mL/min/1.73 m². However, he has dipstick-positive proteinuria, which, if confirmed on further testing, would meet the criteria for chronic kidney disease and put him at a higher risk of cardiovascular events and progression to lower kidney function than the patient in case 1. He also needs to be screened for undiagnosed hypertension and underlying glomerular disease.

REFERRAL TO (AND COLLABORATION WITH) A NEPHROLOGIST

Effective co-management with a nephrologist is essential for the overall health of the patient with chronic kidney disease, as well as slowing the progression to end-stage renal disease. Exactly when and to what extent the care of a patient with chronic kidney disease should be transferred to a nephrologist depends largely on the individual nephrologist and the comfort level of the primary care provider. When the referral does occur, effective communication between providers and a mutual understanding of the goals of care (eg, the blood pressure target) are essential to optimize patient care.

Chronic kidney disease is most often discovered and diagnosed by primary care providers. The equations for estimating the glomerular filtration rate (GFR) facilitate earlier detection of this disease. However, the estimated GFR must be interpreted in the context of the individual patient. The diagnostic criteria and staging of chronic kidney disease must be understood so that it can be recognized and managed at the earliest possible stage. In this way, primary care physicians and nephrologists can better coordinate the care of these patients.

THE STAGES OF RENAL DISEASE AND THE GFR

Before 2002, an organized approach to the clinical management of patients with renal dysfunction was hampered by a lack of a standardized way to define this condition. This changed when the National Kidney Foundation, through the Kidney Disease Outcomes Quality Initiative (K/DOQI),¹ defined the stages of chronic kidney disease based on the GFR as estimated by the Modification of Diet in Renal Disease (MDRD) equation.^2,3

See related editorial

This system has increased the recognition of chronic kidney disease by the health care community and the general public. But the entire system hinges on the utility, accuracy, and reliability of the equations used to estimate the GFR.

In this article, we review the concepts of renal clearance and how to interpret the GFR in healthy patients and in those with chronic kidney disease. The following cases illustrate the interpretation of GFR in the context of patient care.

CASE 1: A 60-YEAR-OLD WOMAN WITH A ‘NORMAL’ CREATININE LEVEL

A 60-year-old white woman with no significant medical history has routine laboratory tests done as part of her annual physical examination. She weighs 135 pounds (61.2 kg) and is 64 inches (163 cm) tall. Her serum creatinine level is 1.1 mg/dL; her estimated GFR is 53 mL/min/1.73 m². A urine dipstick test for protein and blood is normal.

CASE 2: PROTEINURIA WITH A PRESERVED GFR

A 20-year-old African American man with no medical history is undergoing routine blood testing. His serum creatinine level is 1.1 mg/dL; his estimated GFR is reported as “> 60 mL/min/1.73 m²” (calculated at 109 mL/min/1.73 m²). He is 72 inches (183 cm) tall and weighs 180 pounds (83.0 kg); he lifts weights four times a week. Urine dipstick testing reveals 3+ proteinuria.

SERUM CREATININE: AN IMPERFECT MARKER OF KIDNEY FUNCTION

Of the various functions of the kidney, the ability of the glomeruli to filter the blood, as assessed by the GFR, is considered the best index of overall kidney function.^4,5 The GFR can be thought of as the clearance of a substance from the plasma by the kidney in a period of time. This is useful because no method is available to routinely and directly measure filtration across the glomerular basement membrane.

Substances that are cleared by the kidney are used to estimate the GFR. The ideal substance for this estimate is one that is cleared only by filtration and not through metabolism or excretion by other means.

The urinary clearance of the exogenous substance inulin is considered the gold standard method, but radioisotopes such as iothalamate and other markers have replaced inulin in clinical laboratories. Because these methods are expensive, time-consuming, and not widely available, alternative methods that use endogenous markers such as creatinine have been developed for clinical practice.

The serum creatinine concentration possesses many of the qualities of an ideal marker for estimating kidney function. Creatinine is produced by the body at a relatively constant rate under normal conditions and is easy and inexpensive to measure. However, it has several limitations:

• 

  Data presented in Rolin HA III, et al. Evaluation of glomerular filtration rate and renal plasma flow. In: Jacobson HR, et al, eds. The Principles and Practice of Nephrology. St. Louis: Mosby-Year Book 1995:8-13.

  Its clearance does not solely reflect glomerular filtration because the renal tubules also excrete it into the urine.⁶ As a result, creatinine clearance (see below) will tend to overestimate the GFR (Figure 1).
• The serum creatinine concentration is directly dependent on muscle mass, which varies with sex (women tend to have less muscle mass as a percent of body weight than men), age (muscle mass decreases with age), and race (African Americans have a higher serum creatinine level for the same GFR than other Americans).⁶ Thus, there is no “normal” value for serum creatinine that applies to all patients.
• 
  Other factors can alter the creatinine level without changing the GFR, such as changes in dietary protein intake, exercise, and drugs such as cimetidine⁷ and fibrates⁸ (Table 1).

Another important point is that the relationship between the serum creatinine concentration and the GFR is parabolic.⁹ At high kidney function, large changes in the GFR are reflected by very small changes in serum creatinine—the GFR must fall quite a bit before the serum creatinine level rises very much (points A to B in Figure 1). At lower kidney function, small changes in GFR are reflected by large changes in serum creatinine (points C to D in Figure 1). This phenomenon can cause physicians to view small changes in creatinine as unimportant in patients with creatinine levels in the normal or near-normal range. Conversely, small changes may be due to random error inherent in the methods of measuring creatinine rather than to changes in kidney function.

Because the serum creatinine concentration by itself may be misleading when estimating GFR, the National Kidney Foundation and the National Kidney Disease Education Program recommend that it not be used on its own to estimate kidney function.

ESTIMATING THE GFR

Measuring 24-hour creatinine clearance

Measuring 24-hour creatinine clearance involves measuring the concentrations of creatinine in the serum and the urine and the volume of urine excreted in 24 hours.

The 24-hour creatinine clearance was long considered the best alternative to the serum creatinine concentration for assessing kidney function, as it adjusts for changes in the creatinine concentration by taking into account creatinine’s excretion in the urine. However, 24-hour urine collection is burdensome for the patient, and the results are not always reliable because of variations in collection technique. Also, using the creatinine clearance does not resolve problems with using the serum creatinine concentration, such as tubular secretion and overestimation of GFR.

In an effort to more easily estimate GFR from blood tests alone, efforts to develop mathematical equations that more closely estimate GFR began over 40 years ago. These equations take into account factors such as age, sex, and ethnicity. The best known of these are the Cockcroft and Gault¹⁰ and the MDRD equations.⁵

The Cockcroft-Gault equation

The Cockcroft-Gault equation is fairly simple, using serum creatinine, ideal body weight, and an adjustment factor for sex. Its main drawbacks are that it was developed to model creatinine clearance, itself an imperfect estimation of GFR, and it depends heavily on the accuracy of the value for “lean” body weight used in the equation.

The MDRD equation

The MDRD equation has now largely replaced the Cockcroft-Gault equation. Developed using iothalamate GFR measurements, it therefore estimates GFR rather than the less-accurate creatinine clearance. Also, it is normalized to a standard body surface area (1.73 m²), obviating the need to determine ideal body weight.

Since the estimated GFR can often be calculated using data available in most electronic medical record systems, it can be reported directly with any laboratory report that includes a serum creatinine value.

The main drawback of the MDRD equation is that it tends to underestimate GFR at higher ranges of kidney function, ie, higher than 60 mL/min/1.73 m²).^3,11

The CKD-EPI equation

The Chronic Kidney Disease Epidemiology Collaboration study (CKD-EPI) equation,¹² published in 2009, is expected to eventually replace the currently used MDRD equation, as it performs better at higher ranges of GFR.

Although the CKD-EPI equation still lacks precision and accuracy, it underestimates GFR to a lesser degree than the MDRD equation in patients with preserved renal function. Also, it was developed with the objective of reporting a specific value even when the estimated GFR is greater than 60 mL/min/1.73 m². (In contrast, when laboratories use the MDRD equation, the recommendation is to report any value above this level as “greater than 60 mL/min/1.73 m²”).

A limitation of all equations that use the serum creatinine concentration to assess kidney function is the assumption that creatinine production is both stable over time and similar among patients. As a result, these equations should not be used in situations in which renal function is changing rapidly, such as in acute kidney injury. Also, they should be used with caution in patients at the extremes of body mass, since they underestimate GFR in very muscular patients (eg, as in case 2) and overestimate GFR in very small patients (eg, as in case 1).

Calculators for estimating the GFR using these equations are available on many Web sites (see www.kidney.org/professionals/kdoqi/gfr_calculator.cfm).

SCREEN EVERYONE AT RISK

In general, anyone at higher risk of chronic kidney disease should be screened for it. This group includes US minorities and patients with hypertension, cardiovascular disease, and diabetes mellitus, among others.¹³ Screening includes an assessment of estimated GFR and urinalysis for proteinuria or hematuria.

CHRONIC KIDNEY DISEASE DEFINED: DAMAGE AND DURATION

The kidney damage can be either parenchymal renal damage independent of GFR (for example, cystic disease, glomerular hematuria, or proteinuria) or depressed GFR independent of evidence of parenchymal renal disease (an estimated GFR of less than 60 mL/min/1.73 m²).

The duration component requires that the abnormality be present for at least 3 months (ie, chronic).

 

 

Concerns about the definition

This definition has not been without controversy.

An unintended consequence of not reporting estimated GFR values above 60 mL/min/1.73 m² in absolute numbers is that providers may ignore changes in serum creatinine at estimated GFRs in this range, as they assume that the kidney function is “normal.” This may change in the future if the CKD-EPI equation is used, which produces less bias at slightly higher GFRs.

Providers may also tend to focus solely on the estimated GFR criterion and ignore other evidence of chronic kidney disease, such as abnormalities in urinalysis or imaging studies. For example, proteinuria has been shown to be more important than absolute GFR values in predicting progression of renal dysfunction and cardiovascular risk.¹⁴ Proteinuria, especially in the setting of an estimated GFR above 60 mL/min/1.73 m², can be missed if not screened for and underappreciated once found.

Moreover, in elderly patients, the current GFR equations underperform at borderline GFR values and can yield depressed values even at impressively “normal” serum creatinine levels. As a result, there is concern that chronic kidney disease is being overdiagnosed under the current system. This is especially worrisome in elderly white women without risk factors for chronic kidney disease (eg, as in case 1).

In addition, the question arises whether the arbitrary cutoff for chronic kidney disease— 60 mL/min/1.73 m²—applies to all populations.^15,16 The utility of classifying someone as having chronic kidney disease who has an estimated GFR of 55 mL/min/1.73 m² and no risk factors for chronic kidney disease (Table 2) should be questioned if the risk of progressing to end-stage renal disease or suffering a cardiovascular event is only minimally higher than in patients with a higher estimated GFR.^6,17 If the true purpose of developing the chronic kidney disease classification system is to improve patient care and outcomes, then it is of no benefit to overclassify such patients. Indeed, the stress induced by the diagnosis and the negative implications on insurance coverage and health care costs may outweigh any benefits.¹⁸

Nevertheless, these concerns do not invalidate the entire chronic kidney disease definition system, but have stimulated current efforts to improve it based on outcomes research.¹⁹

CASES REVISITED

Case 1: Problems with estimating GFR in a small woman

Case 1 has several points to note.

The patient’s small body size reflects low-level creatinine production. It is not atypical to find serum creatinine levels of 0.5 mg/dL in such patients. Thus, her serum creatinine level of 1.1 mg/dL may be abnormal. The fact that the MDRD equation “normalizes” the result to 1.73 m² of body surface area in patients with very low muscle mass will lead to an overestimation of GFR. However, she has no risk factors for chronic kidney disease.

Additionally, in up to two-thirds of patients kidney function declines with age.²⁰ Whether or not this is “normal aging” of the kidney, it is not clear that this decline in GFR reflects an underlying pathologic process.

Finally, since the patient is an older white woman, the estimated GFR tends to underestimate the true GFR. So while her body size may predispose to an overestimation of GFR, her age, race, and sex predispose to an underestimation of GFR. Many nephrologists would simply order urinalysis and ultrasonography to rule out other evidence of renal dysfunction, then recommend routine monitoring of kidney function in this case.

Case 2: Proteinuria is not normal

In case 2, because the patient is African American, young, and male, his creatinine level yields a higher estimated GFR than in case 1, despite having the same value. However, his estimated GFR still underestimates his true GFR because of his greater creatinine production due to his muscular physique.

This patient subsequently underwent iothalamate GFR testing, which yielded a GFR of 115 mL/min/1.73 m². However, he has dipstick-positive proteinuria, which, if confirmed on further testing, would meet the criteria for chronic kidney disease and put him at a higher risk of cardiovascular events and progression to lower kidney function than the patient in case 1. He also needs to be screened for undiagnosed hypertension and underlying glomerular disease.

REFERRAL TO (AND COLLABORATION WITH) A NEPHROLOGIST

Effective co-management with a nephrologist is essential for the overall health of the patient with chronic kidney disease, as well as slowing the progression to end-stage renal disease. Exactly when and to what extent the care of a patient with chronic kidney disease should be transferred to a nephrologist depends largely on the individual nephrologist and the comfort level of the primary care provider. When the referral does occur, effective communication between providers and a mutual understanding of the goals of care (eg, the blood pressure target) are essential to optimize patient care.

Chronic kidney disease is most often discovered and diagnosed by primary care providers. The equations for estimating the glomerular filtration rate (GFR) facilitate earlier detection of this disease. However, the estimated GFR must be interpreted in the context of the individual patient. The diagnostic criteria and staging of chronic kidney disease must be understood so that it can be recognized and managed at the earliest possible stage. In this way, primary care physicians and nephrologists can better coordinate the care of these patients.

THE STAGES OF RENAL DISEASE AND THE GFR

Before 2002, an organized approach to the clinical management of patients with renal dysfunction was hampered by a lack of a standardized way to define this condition. This changed when the National Kidney Foundation, through the Kidney Disease Outcomes Quality Initiative (K/DOQI),¹ defined the stages of chronic kidney disease based on the GFR as estimated by the Modification of Diet in Renal Disease (MDRD) equation.^2,3

See related editorial

This system has increased the recognition of chronic kidney disease by the health care community and the general public. But the entire system hinges on the utility, accuracy, and reliability of the equations used to estimate the GFR.

In this article, we review the concepts of renal clearance and how to interpret the GFR in healthy patients and in those with chronic kidney disease. The following cases illustrate the interpretation of GFR in the context of patient care.

CASE 1: A 60-YEAR-OLD WOMAN WITH A ‘NORMAL’ CREATININE LEVEL

A 60-year-old white woman with no significant medical history has routine laboratory tests done as part of her annual physical examination. She weighs 135 pounds (61.2 kg) and is 64 inches (163 cm) tall. Her serum creatinine level is 1.1 mg/dL; her estimated GFR is 53 mL/min/1.73 m². A urine dipstick test for protein and blood is normal.

CASE 2: PROTEINURIA WITH A PRESERVED GFR

A 20-year-old African American man with no medical history is undergoing routine blood testing. His serum creatinine level is 1.1 mg/dL; his estimated GFR is reported as “> 60 mL/min/1.73 m²” (calculated at 109 mL/min/1.73 m²). He is 72 inches (183 cm) tall and weighs 180 pounds (83.0 kg); he lifts weights four times a week. Urine dipstick testing reveals 3+ proteinuria.

SERUM CREATININE: AN IMPERFECT MARKER OF KIDNEY FUNCTION

Of the various functions of the kidney, the ability of the glomeruli to filter the blood, as assessed by the GFR, is considered the best index of overall kidney function.^4,5 The GFR can be thought of as the clearance of a substance from the plasma by the kidney in a period of time. This is useful because no method is available to routinely and directly measure filtration across the glomerular basement membrane.

Substances that are cleared by the kidney are used to estimate the GFR. The ideal substance for this estimate is one that is cleared only by filtration and not through metabolism or excretion by other means.

The urinary clearance of the exogenous substance inulin is considered the gold standard method, but radioisotopes such as iothalamate and other markers have replaced inulin in clinical laboratories. Because these methods are expensive, time-consuming, and not widely available, alternative methods that use endogenous markers such as creatinine have been developed for clinical practice.

The serum creatinine concentration possesses many of the qualities of an ideal marker for estimating kidney function. Creatinine is produced by the body at a relatively constant rate under normal conditions and is easy and inexpensive to measure. However, it has several limitations:

• 

  Data presented in Rolin HA III, et al. Evaluation of glomerular filtration rate and renal plasma flow. In: Jacobson HR, et al, eds. The Principles and Practice of Nephrology. St. Louis: Mosby-Year Book 1995:8-13.

  Its clearance does not solely reflect glomerular filtration because the renal tubules also excrete it into the urine.⁶ As a result, creatinine clearance (see below) will tend to overestimate the GFR (Figure 1).
• The serum creatinine concentration is directly dependent on muscle mass, which varies with sex (women tend to have less muscle mass as a percent of body weight than men), age (muscle mass decreases with age), and race (African Americans have a higher serum creatinine level for the same GFR than other Americans).⁶ Thus, there is no “normal” value for serum creatinine that applies to all patients.
• 
  Other factors can alter the creatinine level without changing the GFR, such as changes in dietary protein intake, exercise, and drugs such as cimetidine⁷ and fibrates⁸ (Table 1).

Another important point is that the relationship between the serum creatinine concentration and the GFR is parabolic.⁹ At high kidney function, large changes in the GFR are reflected by very small changes in serum creatinine—the GFR must fall quite a bit before the serum creatinine level rises very much (points A to B in Figure 1). At lower kidney function, small changes in GFR are reflected by large changes in serum creatinine (points C to D in Figure 1). This phenomenon can cause physicians to view small changes in creatinine as unimportant in patients with creatinine levels in the normal or near-normal range. Conversely, small changes may be due to random error inherent in the methods of measuring creatinine rather than to changes in kidney function.

Because the serum creatinine concentration by itself may be misleading when estimating GFR, the National Kidney Foundation and the National Kidney Disease Education Program recommend that it not be used on its own to estimate kidney function.

ESTIMATING THE GFR

Measuring 24-hour creatinine clearance

Measuring 24-hour creatinine clearance involves measuring the concentrations of creatinine in the serum and the urine and the volume of urine excreted in 24 hours.

The 24-hour creatinine clearance was long considered the best alternative to the serum creatinine concentration for assessing kidney function, as it adjusts for changes in the creatinine concentration by taking into account creatinine’s excretion in the urine. However, 24-hour urine collection is burdensome for the patient, and the results are not always reliable because of variations in collection technique. Also, using the creatinine clearance does not resolve problems with using the serum creatinine concentration, such as tubular secretion and overestimation of GFR.

In an effort to more easily estimate GFR from blood tests alone, efforts to develop mathematical equations that more closely estimate GFR began over 40 years ago. These equations take into account factors such as age, sex, and ethnicity. The best known of these are the Cockcroft and Gault¹⁰ and the MDRD equations.⁵

The Cockcroft-Gault equation

The Cockcroft-Gault equation is fairly simple, using serum creatinine, ideal body weight, and an adjustment factor for sex. Its main drawbacks are that it was developed to model creatinine clearance, itself an imperfect estimation of GFR, and it depends heavily on the accuracy of the value for “lean” body weight used in the equation.

The MDRD equation

The MDRD equation has now largely replaced the Cockcroft-Gault equation. Developed using iothalamate GFR measurements, it therefore estimates GFR rather than the less-accurate creatinine clearance. Also, it is normalized to a standard body surface area (1.73 m²), obviating the need to determine ideal body weight.

Since the estimated GFR can often be calculated using data available in most electronic medical record systems, it can be reported directly with any laboratory report that includes a serum creatinine value.

The main drawback of the MDRD equation is that it tends to underestimate GFR at higher ranges of kidney function, ie, higher than 60 mL/min/1.73 m²).^3,11

The CKD-EPI equation

The Chronic Kidney Disease Epidemiology Collaboration study (CKD-EPI) equation,¹² published in 2009, is expected to eventually replace the currently used MDRD equation, as it performs better at higher ranges of GFR.

Although the CKD-EPI equation still lacks precision and accuracy, it underestimates GFR to a lesser degree than the MDRD equation in patients with preserved renal function. Also, it was developed with the objective of reporting a specific value even when the estimated GFR is greater than 60 mL/min/1.73 m². (In contrast, when laboratories use the MDRD equation, the recommendation is to report any value above this level as “greater than 60 mL/min/1.73 m²”).

A limitation of all equations that use the serum creatinine concentration to assess kidney function is the assumption that creatinine production is both stable over time and similar among patients. As a result, these equations should not be used in situations in which renal function is changing rapidly, such as in acute kidney injury. Also, they should be used with caution in patients at the extremes of body mass, since they underestimate GFR in very muscular patients (eg, as in case 2) and overestimate GFR in very small patients (eg, as in case 1).

Calculators for estimating the GFR using these equations are available on many Web sites (see www.kidney.org/professionals/kdoqi/gfr_calculator.cfm).

SCREEN EVERYONE AT RISK

In general, anyone at higher risk of chronic kidney disease should be screened for it. This group includes US minorities and patients with hypertension, cardiovascular disease, and diabetes mellitus, among others.¹³ Screening includes an assessment of estimated GFR and urinalysis for proteinuria or hematuria.

CHRONIC KIDNEY DISEASE DEFINED: DAMAGE AND DURATION

The kidney damage can be either parenchymal renal damage independent of GFR (for example, cystic disease, glomerular hematuria, or proteinuria) or depressed GFR independent of evidence of parenchymal renal disease (an estimated GFR of less than 60 mL/min/1.73 m²).

The duration component requires that the abnormality be present for at least 3 months (ie, chronic).

 

 

Concerns about the definition

This definition has not been without controversy.

An unintended consequence of not reporting estimated GFR values above 60 mL/min/1.73 m² in absolute numbers is that providers may ignore changes in serum creatinine at estimated GFRs in this range, as they assume that the kidney function is “normal.” This may change in the future if the CKD-EPI equation is used, which produces less bias at slightly higher GFRs.

Providers may also tend to focus solely on the estimated GFR criterion and ignore other evidence of chronic kidney disease, such as abnormalities in urinalysis or imaging studies. For example, proteinuria has been shown to be more important than absolute GFR values in predicting progression of renal dysfunction and cardiovascular risk.¹⁴ Proteinuria, especially in the setting of an estimated GFR above 60 mL/min/1.73 m², can be missed if not screened for and underappreciated once found.

Moreover, in elderly patients, the current GFR equations underperform at borderline GFR values and can yield depressed values even at impressively “normal” serum creatinine levels. As a result, there is concern that chronic kidney disease is being overdiagnosed under the current system. This is especially worrisome in elderly white women without risk factors for chronic kidney disease (eg, as in case 1).

In addition, the question arises whether the arbitrary cutoff for chronic kidney disease— 60 mL/min/1.73 m²—applies to all populations.^15,16 The utility of classifying someone as having chronic kidney disease who has an estimated GFR of 55 mL/min/1.73 m² and no risk factors for chronic kidney disease (Table 2) should be questioned if the risk of progressing to end-stage renal disease or suffering a cardiovascular event is only minimally higher than in patients with a higher estimated GFR.^6,17 If the true purpose of developing the chronic kidney disease classification system is to improve patient care and outcomes, then it is of no benefit to overclassify such patients. Indeed, the stress induced by the diagnosis and the negative implications on insurance coverage and health care costs may outweigh any benefits.¹⁸

Nevertheless, these concerns do not invalidate the entire chronic kidney disease definition system, but have stimulated current efforts to improve it based on outcomes research.¹⁹

CASES REVISITED

Case 1: Problems with estimating GFR in a small woman

Case 1 has several points to note.

The patient’s small body size reflects low-level creatinine production. It is not atypical to find serum creatinine levels of 0.5 mg/dL in such patients. Thus, her serum creatinine level of 1.1 mg/dL may be abnormal. The fact that the MDRD equation “normalizes” the result to 1.73 m² of body surface area in patients with very low muscle mass will lead to an overestimation of GFR. However, she has no risk factors for chronic kidney disease.

Additionally, in up to two-thirds of patients kidney function declines with age.²⁰ Whether or not this is “normal aging” of the kidney, it is not clear that this decline in GFR reflects an underlying pathologic process.

Finally, since the patient is an older white woman, the estimated GFR tends to underestimate the true GFR. So while her body size may predispose to an overestimation of GFR, her age, race, and sex predispose to an underestimation of GFR. Many nephrologists would simply order urinalysis and ultrasonography to rule out other evidence of renal dysfunction, then recommend routine monitoring of kidney function in this case.

Case 2: Proteinuria is not normal

In case 2, because the patient is African American, young, and male, his creatinine level yields a higher estimated GFR than in case 1, despite having the same value. However, his estimated GFR still underestimates his true GFR because of his greater creatinine production due to his muscular physique.

This patient subsequently underwent iothalamate GFR testing, which yielded a GFR of 115 mL/min/1.73 m². However, he has dipstick-positive proteinuria, which, if confirmed on further testing, would meet the criteria for chronic kidney disease and put him at a higher risk of cardiovascular events and progression to lower kidney function than the patient in case 1. He also needs to be screened for undiagnosed hypertension and underlying glomerular disease.

REFERRAL TO (AND COLLABORATION WITH) A NEPHROLOGIST

Effective co-management with a nephrologist is essential for the overall health of the patient with chronic kidney disease, as well as slowing the progression to end-stage renal disease. Exactly when and to what extent the care of a patient with chronic kidney disease should be transferred to a nephrologist depends largely on the individual nephrologist and the comfort level of the primary care provider. When the referral does occur, effective communication between providers and a mutual understanding of the goals of care (eg, the blood pressure target) are essential to optimize patient care.

ORLANDO – Pomegranate extract slowed prostate-specific antigen doubling time by more than 6 months in a broad population of patients with prostate cancer, but there was also a worrisome signal that it may accelerate the disease in some.

Photo credit: Irochka/Fotalia.com

Overall, the median pretreatment PSA doubling time (PSADT) increased significantly from 11.9 months to 18.5 months post treatment (P less than .001) among 92 evaluable men with a rising PSA after primary therapy in the phase II, double-blind, multicenter study.

The increase in median PSADT was similar whether the men were randomized to one capsule daily (from 11.9 to 18 months) or to three capsules daily (from 12.2 to 17.5 months). A negative PSA slope, suggesting declining PSA values, was observed in 13% of patients, reported Dr. Michael Carducci, a professor of oncology and urology at Johns Hopkins University in Baltimore.

Nearly 20% of the population, however, had their PSADTs shortened, leading to treatment discontinuation.

"There is an apparent benefit across all PSA doubling times, although some shortening of PSA doubling time was seen," Dr. Carducci said at the Genitourinary Cancers Symposium.

Invited discussant Dr. Michael J. Morris of Memorial Sloan-Kettering Cancer Center in New York said that the study’s end point has never been prospectively validated to show anything in terms of clinical outcome.

"If you believe that prolonged PSA doubling time is clinically beneficial, what do we say about patients whose disease appears to accelerate as a result of taking the pomegranate extract?" he asked. "Do we say or suggest that a third to 40% of patients might be done some harm, or might have an earlier clinical end point? I don’t know, but I think that’s an issue of concern."

In an interview, Dr. Carducci said that Dr. Morris’s estimate appears to include anyone with a faster PSADT, but that a fair number of these cases occurred at baseline, with only 14 patients moving to a faster PSADT quartile during treatment.

"Whether chemotherapy or a natural product like this is used, sometimes it appears that the disease picks up," he said. "The relevance is that they come off treatment, and we could detect no clinical impact on those whose PSADT shortened."

During his presentation, Dr. Carducci acknowledged that the study was limited by the lack of a placebo, and that a number of reports in the literature – including studies of rosiglitazone (Avandia) and atrasentan (Xinlay) – have shown that placebo can slow PSADT.

"We did not have a placebo, so [these data are not] definitive and could be explained by on-study regression to the mean," he said, noting that data should be available in the near future from a 200-patient, placebo-controlled trial of pomegranate extract liquid.

A previous phase II study reported that 8 ounces of pomegranate juice per day increased PSADT more than threefold, from a mean of 15 months to 54 months post treatment in 48 men with a rising PSA after surgery or radiation (Clin. Cancer Res. 2006;12:4018-26). The study was limited to men who had a narrow baseline PSA level of more than 0.2 ng/mL but less than 5 ng/mL, and a Gleason score of 7 or less.

There are laboratory data to show that pomegranate extract more effectively controls the growth of prostate cancer than does pomegranate juice in prostate cancer cell lines, but no head-to-head comparison has been tested in patients, Dr. Carducci said.

In an effort to evaluate the extract in a broader patient population, the current study in 104 men allowed any type of primary local therapy, any PSA that was rising from a baseline level of at least 0.4 ng/mL, and any Gleason score.

The 101 men in the intent-to-treat analysis had a median Gleason score of 7, and about one-third of them had a baseline PSADT of 9 months or less. (Three patients were excluded from the intent-to-treat analysis because they did not have postbaseline PSADT. In addition, 8 men were dropped from the evaluable population of 92 men because they did not meet PSA entry criteria, and 1 took prohibited medication.)

The men were treated for up to 6 months (92% of patients), 12 months (70%), or 18 months (36%) with capsules containing 1,000 mg of pomegranate polyphenol, equivalent to 8 ounces of pomegranate juice. In all, 58% of patients completed the 18-month, double-blind portion of the study, and 42% discontinued treatment before progression, Dr. Carducci said.

There were no grade 3 or 4 toxicities. Mild to moderate diarrhea was reported in 1.9% of patients who took one capsule daily and in 13.5% of those taking three capsules daily. There were no significant changes in testosterone from the baseline value of more than 1.5 ng/mL.

Ultimately, the decision to use pomegranate extract or juice is a matter of discussion between physician and patient, Dr. Carducci said in the interview.

"I think with two consistent data sets showing slowing PSA doubling time, it would be reasonable for a patient to consider and understand what he’s getting himself into," he said. "It’s possible that patients with slower growing disease may have the greater benefit."

The meeting was sponsored by the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology. Dr. Carducci is an unpaid consultant for and has received research funding from the study sponsor, POM Wonderful. Dr. Morris disclosed relationships with nine companies.

ORLANDO – Pomegranate extract slowed prostate-specific antigen doubling time by more than 6 months in a broad population of patients with prostate cancer, but there was also a worrisome signal that it may accelerate the disease in some.

Photo credit: Irochka/Fotalia.com

Overall, the median pretreatment PSA doubling time (PSADT) increased significantly from 11.9 months to 18.5 months post treatment (P less than .001) among 92 evaluable men with a rising PSA after primary therapy in the phase II, double-blind, multicenter study.

The increase in median PSADT was similar whether the men were randomized to one capsule daily (from 11.9 to 18 months) or to three capsules daily (from 12.2 to 17.5 months). A negative PSA slope, suggesting declining PSA values, was observed in 13% of patients, reported Dr. Michael Carducci, a professor of oncology and urology at Johns Hopkins University in Baltimore.

Nearly 20% of the population, however, had their PSADTs shortened, leading to treatment discontinuation.

"There is an apparent benefit across all PSA doubling times, although some shortening of PSA doubling time was seen," Dr. Carducci said at the Genitourinary Cancers Symposium.

Invited discussant Dr. Michael J. Morris of Memorial Sloan-Kettering Cancer Center in New York said that the study’s end point has never been prospectively validated to show anything in terms of clinical outcome.

"If you believe that prolonged PSA doubling time is clinically beneficial, what do we say about patients whose disease appears to accelerate as a result of taking the pomegranate extract?" he asked. "Do we say or suggest that a third to 40% of patients might be done some harm, or might have an earlier clinical end point? I don’t know, but I think that’s an issue of concern."

In an interview, Dr. Carducci said that Dr. Morris’s estimate appears to include anyone with a faster PSADT, but that a fair number of these cases occurred at baseline, with only 14 patients moving to a faster PSADT quartile during treatment.

"Whether chemotherapy or a natural product like this is used, sometimes it appears that the disease picks up," he said. "The relevance is that they come off treatment, and we could detect no clinical impact on those whose PSADT shortened."

During his presentation, Dr. Carducci acknowledged that the study was limited by the lack of a placebo, and that a number of reports in the literature – including studies of rosiglitazone (Avandia) and atrasentan (Xinlay) – have shown that placebo can slow PSADT.

"We did not have a placebo, so [these data are not] definitive and could be explained by on-study regression to the mean," he said, noting that data should be available in the near future from a 200-patient, placebo-controlled trial of pomegranate extract liquid.

A previous phase II study reported that 8 ounces of pomegranate juice per day increased PSADT more than threefold, from a mean of 15 months to 54 months post treatment in 48 men with a rising PSA after surgery or radiation (Clin. Cancer Res. 2006;12:4018-26). The study was limited to men who had a narrow baseline PSA level of more than 0.2 ng/mL but less than 5 ng/mL, and a Gleason score of 7 or less.

There are laboratory data to show that pomegranate extract more effectively controls the growth of prostate cancer than does pomegranate juice in prostate cancer cell lines, but no head-to-head comparison has been tested in patients, Dr. Carducci said.

In an effort to evaluate the extract in a broader patient population, the current study in 104 men allowed any type of primary local therapy, any PSA that was rising from a baseline level of at least 0.4 ng/mL, and any Gleason score.

The 101 men in the intent-to-treat analysis had a median Gleason score of 7, and about one-third of them had a baseline PSADT of 9 months or less. (Three patients were excluded from the intent-to-treat analysis because they did not have postbaseline PSADT. In addition, 8 men were dropped from the evaluable population of 92 men because they did not meet PSA entry criteria, and 1 took prohibited medication.)

The men were treated for up to 6 months (92% of patients), 12 months (70%), or 18 months (36%) with capsules containing 1,000 mg of pomegranate polyphenol, equivalent to 8 ounces of pomegranate juice. In all, 58% of patients completed the 18-month, double-blind portion of the study, and 42% discontinued treatment before progression, Dr. Carducci said.

There were no grade 3 or 4 toxicities. Mild to moderate diarrhea was reported in 1.9% of patients who took one capsule daily and in 13.5% of those taking three capsules daily. There were no significant changes in testosterone from the baseline value of more than 1.5 ng/mL.

Ultimately, the decision to use pomegranate extract or juice is a matter of discussion between physician and patient, Dr. Carducci said in the interview.

"I think with two consistent data sets showing slowing PSA doubling time, it would be reasonable for a patient to consider and understand what he’s getting himself into," he said. "It’s possible that patients with slower growing disease may have the greater benefit."

The meeting was sponsored by the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology. Dr. Carducci is an unpaid consultant for and has received research funding from the study sponsor, POM Wonderful. Dr. Morris disclosed relationships with nine companies.

ORLANDO – Pomegranate extract slowed prostate-specific antigen doubling time by more than 6 months in a broad population of patients with prostate cancer, but there was also a worrisome signal that it may accelerate the disease in some.

Photo credit: Irochka/Fotalia.com

Overall, the median pretreatment PSA doubling time (PSADT) increased significantly from 11.9 months to 18.5 months post treatment (P less than .001) among 92 evaluable men with a rising PSA after primary therapy in the phase II, double-blind, multicenter study.

The increase in median PSADT was similar whether the men were randomized to one capsule daily (from 11.9 to 18 months) or to three capsules daily (from 12.2 to 17.5 months). A negative PSA slope, suggesting declining PSA values, was observed in 13% of patients, reported Dr. Michael Carducci, a professor of oncology and urology at Johns Hopkins University in Baltimore.

Nearly 20% of the population, however, had their PSADTs shortened, leading to treatment discontinuation.

"There is an apparent benefit across all PSA doubling times, although some shortening of PSA doubling time was seen," Dr. Carducci said at the Genitourinary Cancers Symposium.

Invited discussant Dr. Michael J. Morris of Memorial Sloan-Kettering Cancer Center in New York said that the study’s end point has never been prospectively validated to show anything in terms of clinical outcome.

"If you believe that prolonged PSA doubling time is clinically beneficial, what do we say about patients whose disease appears to accelerate as a result of taking the pomegranate extract?" he asked. "Do we say or suggest that a third to 40% of patients might be done some harm, or might have an earlier clinical end point? I don’t know, but I think that’s an issue of concern."

In an interview, Dr. Carducci said that Dr. Morris’s estimate appears to include anyone with a faster PSADT, but that a fair number of these cases occurred at baseline, with only 14 patients moving to a faster PSADT quartile during treatment.

"Whether chemotherapy or a natural product like this is used, sometimes it appears that the disease picks up," he said. "The relevance is that they come off treatment, and we could detect no clinical impact on those whose PSADT shortened."

During his presentation, Dr. Carducci acknowledged that the study was limited by the lack of a placebo, and that a number of reports in the literature – including studies of rosiglitazone (Avandia) and atrasentan (Xinlay) – have shown that placebo can slow PSADT.

"We did not have a placebo, so [these data are not] definitive and could be explained by on-study regression to the mean," he said, noting that data should be available in the near future from a 200-patient, placebo-controlled trial of pomegranate extract liquid.

A previous phase II study reported that 8 ounces of pomegranate juice per day increased PSADT more than threefold, from a mean of 15 months to 54 months post treatment in 48 men with a rising PSA after surgery or radiation (Clin. Cancer Res. 2006;12:4018-26). The study was limited to men who had a narrow baseline PSA level of more than 0.2 ng/mL but less than 5 ng/mL, and a Gleason score of 7 or less.

There are laboratory data to show that pomegranate extract more effectively controls the growth of prostate cancer than does pomegranate juice in prostate cancer cell lines, but no head-to-head comparison has been tested in patients, Dr. Carducci said.

In an effort to evaluate the extract in a broader patient population, the current study in 104 men allowed any type of primary local therapy, any PSA that was rising from a baseline level of at least 0.4 ng/mL, and any Gleason score.

The 101 men in the intent-to-treat analysis had a median Gleason score of 7, and about one-third of them had a baseline PSADT of 9 months or less. (Three patients were excluded from the intent-to-treat analysis because they did not have postbaseline PSADT. In addition, 8 men were dropped from the evaluable population of 92 men because they did not meet PSA entry criteria, and 1 took prohibited medication.)

The men were treated for up to 6 months (92% of patients), 12 months (70%), or 18 months (36%) with capsules containing 1,000 mg of pomegranate polyphenol, equivalent to 8 ounces of pomegranate juice. In all, 58% of patients completed the 18-month, double-blind portion of the study, and 42% discontinued treatment before progression, Dr. Carducci said.

There were no grade 3 or 4 toxicities. Mild to moderate diarrhea was reported in 1.9% of patients who took one capsule daily and in 13.5% of those taking three capsules daily. There were no significant changes in testosterone from the baseline value of more than 1.5 ng/mL.

Ultimately, the decision to use pomegranate extract or juice is a matter of discussion between physician and patient, Dr. Carducci said in the interview.

"I think with two consistent data sets showing slowing PSA doubling time, it would be reasonable for a patient to consider and understand what he’s getting himself into," he said. "It’s possible that patients with slower growing disease may have the greater benefit."

The meeting was sponsored by the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology. Dr. Carducci is an unpaid consultant for and has received research funding from the study sponsor, POM Wonderful. Dr. Morris disclosed relationships with nine companies.

ORLANDO – Adding the investigational agent vandetanib to docetaxel added toxicity but little clinical benefit in a double-blind, multicenter study of 142 patients with platinum-pretreated metastatic urothelial cancer.

The primary end point of median progression-free survival reached 1.58 months with placebo plus docetaxel (Taxotere) and 2.56 months with vandetanib plus docetaxel (hazard ratio 1.02). Median overall survival was actually longer with placebo at 7.03 months vs. 5.85 months with vandetanib (HR 1.21).

Treatment-related all-grade toxicity was reported in 66% of the vandetanib vs. 44% in the placebo arm (P = .012), and high-grade toxicity in 60% vs. 36% (P = .007), lead author Dr. Toni K. Choueiri reported in a late-breaking abstract at the Genitourinary Cancers Symposium.

"The addition of vandetanib, a dual EGFR/VEGFR antagonist, to docetaxel did not result in any benefit in terms of progression-free survival, response rate, or overall survival as compared to placebo plus docetaxel," he concluded. "Toxicities ran higher, but [were] manageable."

Vandetanib was an attractive agent to evaluate because it blocks the tyrosine kinase activity of epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) receptor 2, two pathways that play an important role in urothelial cancer.

The researchers had hypothesized that simultaneous blockade of the pathways, in addition to the taxane docetaxel, might provide additional benefit, compared with chemotherapy alone. There is no standard of care for metastatic urothelial cancer that has progressed after treatment with a platinum-containing regimen. Taxanes often are used in the salvage setting, but with minimal activity, he said.

AstraZeneca is seeking approval of vandetanib for the treatment of unresectable locally advanced or metastatic medullary thyroid cancer. A Food and Drug Administration panel voted in late December that the risk-benefit profile of vandetanib is acceptable for patients with progressive, symptomatic medullary thyroid cancer, and added restrictive language to the proposed indication in light of toxicity concerns, particularly the possibility of QTc prolongation. On Jan. 7, the FDA extended the review time line for the new drug application to April 7, 2011.

In 2009, AstraZeneca filed for an advanced non–small cell lung cancer indication for vandetanib (under the proposed trade name Zactima) in the United States and Europe, but quickly withdrew the applications after preliminary feedback from regulators indicated progression-free survival data were not sufficient to support approval.

Dr. Choueiri and his associates assessed long-term outcomes among 142 patients with metastatic bladder cancer who had failed first-line platinum-based chemotherapy and received up to three prior systemic therapies including paclitaxel. They had a performance status of 0 or 1, and brain metastases were allowed.

Patients were randomized to docetaxel 75 mg/m² every 21 days plus oral vandetanib 100 mg once daily or the same docetaxel regimen plus oral placebo until disease progression. Patients on the placebo arm were allowed to cross over to single-agent vandetanib.

Only 8 of the 72 (11%) placebo patients and 5 of the 70 (7%) vandetanib patients responded to treatment, Dr. Choueiri reported.

In all, 25% of the placebo arm experienced a grade 3/4 treatment-related nonhematologic adverse event vs. 50% of the vandetanib arm, including significantly more rash/photosensitivity (11% vs. 0%) and diarrhea (7% vs. 0%).

Single-agent activity with vandetanib was limited, said Dr. Choueiri, with the Dana-Farber Cancer Institute and Harvard Medical School, both in Boston. A crossover analysis among 37 patients revealed one partial response and stable disease in 5 patients, with a median overall survival of 5.2 months. Two patients were unevaluable, and one patient recently crossed over without response data.

Exploratory analyses among all patients revealed no preferential activity with vandetanib for any subgroup with regard to progression-free or overall survival, Dr. Choueiri said.

"Clinical trials of rational drugs and combinations are urgently needed in this setting," he said.

The Dana-Farber Cancer Institute sponsored the study. Dr. Choueiri reported consultant/advisory roles with Bayer, Genentech, GlaxoSmithKline, Novartis, Onyx Pharmaceuticals, and Pfizer.

ORLANDO – Adding the investigational agent vandetanib to docetaxel added toxicity but little clinical benefit in a double-blind, multicenter study of 142 patients with platinum-pretreated metastatic urothelial cancer.

The primary end point of median progression-free survival reached 1.58 months with placebo plus docetaxel (Taxotere) and 2.56 months with vandetanib plus docetaxel (hazard ratio 1.02). Median overall survival was actually longer with placebo at 7.03 months vs. 5.85 months with vandetanib (HR 1.21).

Treatment-related all-grade toxicity was reported in 66% of the vandetanib vs. 44% in the placebo arm (P = .012), and high-grade toxicity in 60% vs. 36% (P = .007), lead author Dr. Toni K. Choueiri reported in a late-breaking abstract at the Genitourinary Cancers Symposium.

"The addition of vandetanib, a dual EGFR/VEGFR antagonist, to docetaxel did not result in any benefit in terms of progression-free survival, response rate, or overall survival as compared to placebo plus docetaxel," he concluded. "Toxicities ran higher, but [were] manageable."

Vandetanib was an attractive agent to evaluate because it blocks the tyrosine kinase activity of epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) receptor 2, two pathways that play an important role in urothelial cancer.

The researchers had hypothesized that simultaneous blockade of the pathways, in addition to the taxane docetaxel, might provide additional benefit, compared with chemotherapy alone. There is no standard of care for metastatic urothelial cancer that has progressed after treatment with a platinum-containing regimen. Taxanes often are used in the salvage setting, but with minimal activity, he said.

AstraZeneca is seeking approval of vandetanib for the treatment of unresectable locally advanced or metastatic medullary thyroid cancer. A Food and Drug Administration panel voted in late December that the risk-benefit profile of vandetanib is acceptable for patients with progressive, symptomatic medullary thyroid cancer, and added restrictive language to the proposed indication in light of toxicity concerns, particularly the possibility of QTc prolongation. On Jan. 7, the FDA extended the review time line for the new drug application to April 7, 2011.

In 2009, AstraZeneca filed for an advanced non–small cell lung cancer indication for vandetanib (under the proposed trade name Zactima) in the United States and Europe, but quickly withdrew the applications after preliminary feedback from regulators indicated progression-free survival data were not sufficient to support approval.

Dr. Choueiri and his associates assessed long-term outcomes among 142 patients with metastatic bladder cancer who had failed first-line platinum-based chemotherapy and received up to three prior systemic therapies including paclitaxel. They had a performance status of 0 or 1, and brain metastases were allowed.

Patients were randomized to docetaxel 75 mg/m² every 21 days plus oral vandetanib 100 mg once daily or the same docetaxel regimen plus oral placebo until disease progression. Patients on the placebo arm were allowed to cross over to single-agent vandetanib.

Only 8 of the 72 (11%) placebo patients and 5 of the 70 (7%) vandetanib patients responded to treatment, Dr. Choueiri reported.

In all, 25% of the placebo arm experienced a grade 3/4 treatment-related nonhematologic adverse event vs. 50% of the vandetanib arm, including significantly more rash/photosensitivity (11% vs. 0%) and diarrhea (7% vs. 0%).

Single-agent activity with vandetanib was limited, said Dr. Choueiri, with the Dana-Farber Cancer Institute and Harvard Medical School, both in Boston. A crossover analysis among 37 patients revealed one partial response and stable disease in 5 patients, with a median overall survival of 5.2 months. Two patients were unevaluable, and one patient recently crossed over without response data.

Exploratory analyses among all patients revealed no preferential activity with vandetanib for any subgroup with regard to progression-free or overall survival, Dr. Choueiri said.

"Clinical trials of rational drugs and combinations are urgently needed in this setting," he said.

The Dana-Farber Cancer Institute sponsored the study. Dr. Choueiri reported consultant/advisory roles with Bayer, Genentech, GlaxoSmithKline, Novartis, Onyx Pharmaceuticals, and Pfizer.

ORLANDO – Adding the investigational agent vandetanib to docetaxel added toxicity but little clinical benefit in a double-blind, multicenter study of 142 patients with platinum-pretreated metastatic urothelial cancer.

The primary end point of median progression-free survival reached 1.58 months with placebo plus docetaxel (Taxotere) and 2.56 months with vandetanib plus docetaxel (hazard ratio 1.02). Median overall survival was actually longer with placebo at 7.03 months vs. 5.85 months with vandetanib (HR 1.21).

Treatment-related all-grade toxicity was reported in 66% of the vandetanib vs. 44% in the placebo arm (P = .012), and high-grade toxicity in 60% vs. 36% (P = .007), lead author Dr. Toni K. Choueiri reported in a late-breaking abstract at the Genitourinary Cancers Symposium.

"The addition of vandetanib, a dual EGFR/VEGFR antagonist, to docetaxel did not result in any benefit in terms of progression-free survival, response rate, or overall survival as compared to placebo plus docetaxel," he concluded. "Toxicities ran higher, but [were] manageable."

Vandetanib was an attractive agent to evaluate because it blocks the tyrosine kinase activity of epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) receptor 2, two pathways that play an important role in urothelial cancer.

The researchers had hypothesized that simultaneous blockade of the pathways, in addition to the taxane docetaxel, might provide additional benefit, compared with chemotherapy alone. There is no standard of care for metastatic urothelial cancer that has progressed after treatment with a platinum-containing regimen. Taxanes often are used in the salvage setting, but with minimal activity, he said.

AstraZeneca is seeking approval of vandetanib for the treatment of unresectable locally advanced or metastatic medullary thyroid cancer. A Food and Drug Administration panel voted in late December that the risk-benefit profile of vandetanib is acceptable for patients with progressive, symptomatic medullary thyroid cancer, and added restrictive language to the proposed indication in light of toxicity concerns, particularly the possibility of QTc prolongation. On Jan. 7, the FDA extended the review time line for the new drug application to April 7, 2011.

In 2009, AstraZeneca filed for an advanced non–small cell lung cancer indication for vandetanib (under the proposed trade name Zactima) in the United States and Europe, but quickly withdrew the applications after preliminary feedback from regulators indicated progression-free survival data were not sufficient to support approval.

Dr. Choueiri and his associates assessed long-term outcomes among 142 patients with metastatic bladder cancer who had failed first-line platinum-based chemotherapy and received up to three prior systemic therapies including paclitaxel. They had a performance status of 0 or 1, and brain metastases were allowed.

Patients were randomized to docetaxel 75 mg/m² every 21 days plus oral vandetanib 100 mg once daily or the same docetaxel regimen plus oral placebo until disease progression. Patients on the placebo arm were allowed to cross over to single-agent vandetanib.

Only 8 of the 72 (11%) placebo patients and 5 of the 70 (7%) vandetanib patients responded to treatment, Dr. Choueiri reported.

In all, 25% of the placebo arm experienced a grade 3/4 treatment-related nonhematologic adverse event vs. 50% of the vandetanib arm, including significantly more rash/photosensitivity (11% vs. 0%) and diarrhea (7% vs. 0%).

Single-agent activity with vandetanib was limited, said Dr. Choueiri, with the Dana-Farber Cancer Institute and Harvard Medical School, both in Boston. A crossover analysis among 37 patients revealed one partial response and stable disease in 5 patients, with a median overall survival of 5.2 months. Two patients were unevaluable, and one patient recently crossed over without response data.

Exploratory analyses among all patients revealed no preferential activity with vandetanib for any subgroup with regard to progression-free or overall survival, Dr. Choueiri said.

"Clinical trials of rational drugs and combinations are urgently needed in this setting," he said.

The Dana-Farber Cancer Institute sponsored the study. Dr. Choueiri reported consultant/advisory roles with Bayer, Genentech, GlaxoSmithKline, Novartis, Onyx Pharmaceuticals, and Pfizer.

ORLANDO – Nanoparticle albumin-bound paclitaxel resulted in an unprecedented single-agent response rate of 32% in metastatic platinum-refractory urothelial cancer in a multicenter phase II study.

Among the 47 patients evaluable for response to nab-paclitaxel (Abraxane), 15 (32%) had a partial response, and 10 (21%) had stable disease, for a disease control rate of 53%.

"This is so far the highest reported single-agent response rate in second-line urothelial cancer," lead author Dr. Srikala S. Sridhar said at the Genitourinary Cancers Symposium. "Time to progression and progression-free survival [are] higher, as is median survival."

The response rate with nab-paclitaxel is in the same range as some second-line combination therapies, with the added benefit of having less toxicity than many of the doublet and triplet combinations, she said.

Based on the results, it may be time to evaluate nab-paclitaxel in the first-line metastatic setting against gemcitabine (Gemzar) and cisplatin, in cisplatin-ineligible patients, in sequential studies either before or after gemcitabine/cisplatin, or with other chemotherapies or targeted therapy, said Dr. Sridhar of Princess Margaret Hospital in Toronto. A phase II trial (NCT00995488) is currently recruiting patients to evaluate the efficacy of a combination of nab-paclitaxel, carboplatin, and gemcitabine for the first-line treatment of metastatic urothelial cancer.

Standard first-line treatment for metastatic urothelial cancer is cisplatin-based chemotherapy. Despite high response rates of 40%-45%, however, most patients relapse, and median survival is only 12-14 months.

There is currently no approved second-line treatment option for urothelial cancer, the fifth most common cancer in North America, with an estimated 14,000 annual deaths.

In nine previous single-agent second-line trials, pemetrexed achieved the highest response rate of 28%, with a median time to progression of 2.9 months and a median survival of 9.6 months (J. Clin. Oncol. 2006;24:3451-7), she said. In nine combination second-line trials, gemcitabine and paclitaxel together achieved the best response rate of 60% and a median survival of 14.4 months (Cancer 2001;92:2993-8).

The median time to disease progression with nab-paclitaxel was 6.0 months, and the median overall survival was 10.8 months, Dr. Sridhar reported.

Factors associated with improved overall survival were, not surprisingly, a hemoglobin level of at least 100 g/L, a performance status of 1 or less, last chemotherapy at least 5 months before treatment, and achieving disease control, either a partial response or stable disease, with nab-paclitaxel.

Patients in the trial had measurable distant or unresectable local urothelial cancer of mixed histology that had progressed on or within 1 year of platinum-based chemotherapy. They had received no prior taxanes for metastatic disease, had a performance status of 0-2, and had a glomerular filtration rate of more than 40 mL/min.

In all, 48 patients received intravenous nab-paclitaxel 260 mg/m2 every 3 weeks until disease progression or intolerable toxicity occurred. The median number of cycles was six. Dose reductions were required in 33% of patients, mostly because of fatigue or neuropathy, she said.

The most common overall toxicities were alopecia (13%), fatigue (12%), pain (12%), neuropathy (10%), dyspnea (3%), and edema (3%). The most common grade 3 toxicity was pain, which was experienced by 23% of patients, but was not all drug related, Dr. Sridhar said at the symposium, cosponsored by the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology. One patient developed grade 4 fatigue.

Nab-paclitaxel is being investigated in a variety of cancers, and is indicated for the treatment of breast cancer that has failed combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy.

Sunnybrook Health Sciences Centre sponsored the trial in collaboration with Abraxis BioScience. Dr. Sridhar and her coauthors reported no relevant financial disclosures.

ORLANDO – Nanoparticle albumin-bound paclitaxel resulted in an unprecedented single-agent response rate of 32% in metastatic platinum-refractory urothelial cancer in a multicenter phase II study.

Among the 47 patients evaluable for response to nab-paclitaxel (Abraxane), 15 (32%) had a partial response, and 10 (21%) had stable disease, for a disease control rate of 53%.

"This is so far the highest reported single-agent response rate in second-line urothelial cancer," lead author Dr. Srikala S. Sridhar said at the Genitourinary Cancers Symposium. "Time to progression and progression-free survival [are] higher, as is median survival."

The response rate with nab-paclitaxel is in the same range as some second-line combination therapies, with the added benefit of having less toxicity than many of the doublet and triplet combinations, she said.

Based on the results, it may be time to evaluate nab-paclitaxel in the first-line metastatic setting against gemcitabine (Gemzar) and cisplatin, in cisplatin-ineligible patients, in sequential studies either before or after gemcitabine/cisplatin, or with other chemotherapies or targeted therapy, said Dr. Sridhar of Princess Margaret Hospital in Toronto. A phase II trial (NCT00995488) is currently recruiting patients to evaluate the efficacy of a combination of nab-paclitaxel, carboplatin, and gemcitabine for the first-line treatment of metastatic urothelial cancer.

Standard first-line treatment for metastatic urothelial cancer is cisplatin-based chemotherapy. Despite high response rates of 40%-45%, however, most patients relapse, and median survival is only 12-14 months.

There is currently no approved second-line treatment option for urothelial cancer, the fifth most common cancer in North America, with an estimated 14,000 annual deaths.

In nine previous single-agent second-line trials, pemetrexed achieved the highest response rate of 28%, with a median time to progression of 2.9 months and a median survival of 9.6 months (J. Clin. Oncol. 2006;24:3451-7), she said. In nine combination second-line trials, gemcitabine and paclitaxel together achieved the best response rate of 60% and a median survival of 14.4 months (Cancer 2001;92:2993-8).

The median time to disease progression with nab-paclitaxel was 6.0 months, and the median overall survival was 10.8 months, Dr. Sridhar reported.

Factors associated with improved overall survival were, not surprisingly, a hemoglobin level of at least 100 g/L, a performance status of 1 or less, last chemotherapy at least 5 months before treatment, and achieving disease control, either a partial response or stable disease, with nab-paclitaxel.

Patients in the trial had measurable distant or unresectable local urothelial cancer of mixed histology that had progressed on or within 1 year of platinum-based chemotherapy. They had received no prior taxanes for metastatic disease, had a performance status of 0-2, and had a glomerular filtration rate of more than 40 mL/min.

In all, 48 patients received intravenous nab-paclitaxel 260 mg/m2 every 3 weeks until disease progression or intolerable toxicity occurred. The median number of cycles was six. Dose reductions were required in 33% of patients, mostly because of fatigue or neuropathy, she said.

The most common overall toxicities were alopecia (13%), fatigue (12%), pain (12%), neuropathy (10%), dyspnea (3%), and edema (3%). The most common grade 3 toxicity was pain, which was experienced by 23% of patients, but was not all drug related, Dr. Sridhar said at the symposium, cosponsored by the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology. One patient developed grade 4 fatigue.

Nab-paclitaxel is being investigated in a variety of cancers, and is indicated for the treatment of breast cancer that has failed combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy.

Sunnybrook Health Sciences Centre sponsored the trial in collaboration with Abraxis BioScience. Dr. Sridhar and her coauthors reported no relevant financial disclosures.

ORLANDO – Nanoparticle albumin-bound paclitaxel resulted in an unprecedented single-agent response rate of 32% in metastatic platinum-refractory urothelial cancer in a multicenter phase II study.

Among the 47 patients evaluable for response to nab-paclitaxel (Abraxane), 15 (32%) had a partial response, and 10 (21%) had stable disease, for a disease control rate of 53%.

"This is so far the highest reported single-agent response rate in second-line urothelial cancer," lead author Dr. Srikala S. Sridhar said at the Genitourinary Cancers Symposium. "Time to progression and progression-free survival [are] higher, as is median survival."

The response rate with nab-paclitaxel is in the same range as some second-line combination therapies, with the added benefit of having less toxicity than many of the doublet and triplet combinations, she said.

Based on the results, it may be time to evaluate nab-paclitaxel in the first-line metastatic setting against gemcitabine (Gemzar) and cisplatin, in cisplatin-ineligible patients, in sequential studies either before or after gemcitabine/cisplatin, or with other chemotherapies or targeted therapy, said Dr. Sridhar of Princess Margaret Hospital in Toronto. A phase II trial (NCT00995488) is currently recruiting patients to evaluate the efficacy of a combination of nab-paclitaxel, carboplatin, and gemcitabine for the first-line treatment of metastatic urothelial cancer.

Standard first-line treatment for metastatic urothelial cancer is cisplatin-based chemotherapy. Despite high response rates of 40%-45%, however, most patients relapse, and median survival is only 12-14 months.

There is currently no approved second-line treatment option for urothelial cancer, the fifth most common cancer in North America, with an estimated 14,000 annual deaths.

In nine previous single-agent second-line trials, pemetrexed achieved the highest response rate of 28%, with a median time to progression of 2.9 months and a median survival of 9.6 months (J. Clin. Oncol. 2006;24:3451-7), she said. In nine combination second-line trials, gemcitabine and paclitaxel together achieved the best response rate of 60% and a median survival of 14.4 months (Cancer 2001;92:2993-8).

The median time to disease progression with nab-paclitaxel was 6.0 months, and the median overall survival was 10.8 months, Dr. Sridhar reported.

Factors associated with improved overall survival were, not surprisingly, a hemoglobin level of at least 100 g/L, a performance status of 1 or less, last chemotherapy at least 5 months before treatment, and achieving disease control, either a partial response or stable disease, with nab-paclitaxel.

Patients in the trial had measurable distant or unresectable local urothelial cancer of mixed histology that had progressed on or within 1 year of platinum-based chemotherapy. They had received no prior taxanes for metastatic disease, had a performance status of 0-2, and had a glomerular filtration rate of more than 40 mL/min.

In all, 48 patients received intravenous nab-paclitaxel 260 mg/m2 every 3 weeks until disease progression or intolerable toxicity occurred. The median number of cycles was six. Dose reductions were required in 33% of patients, mostly because of fatigue or neuropathy, she said.

The most common overall toxicities were alopecia (13%), fatigue (12%), pain (12%), neuropathy (10%), dyspnea (3%), and edema (3%). The most common grade 3 toxicity was pain, which was experienced by 23% of patients, but was not all drug related, Dr. Sridhar said at the symposium, cosponsored by the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology. One patient developed grade 4 fatigue.

Nab-paclitaxel is being investigated in a variety of cancers, and is indicated for the treatment of breast cancer that has failed combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy.

Sunnybrook Health Sciences Centre sponsored the trial in collaboration with Abraxis BioScience. Dr. Sridhar and her coauthors reported no relevant financial disclosures.

ORLANDO – Nanoparticle albumin-bound paclitaxel resulted in an unprecedented single-agent response rate of 32% in metastatic platinum-refractory urothelial cancer in a multicenter phase II study.

Among the 47 patients evaluable for response to nab-paclitaxel (Abraxane), 15 (32%) had a partial response, and 10 (21%) had stable disease, for a disease control rate of 53%.

"This is so far the highest reported single-agent response rate in second-line urothelial cancer," lead author Dr. Srikala S. Sridhar said at the Genitourinary Cancers Symposium. "Time to progression and progression-free survival [are] higher, as is median survival."

The response rate with nab-paclitaxel is in the same range as some second-line combination therapies, with the added benefit of having less toxicity than many of the doublet and triplet combinations, she said.

Based on the results, it may be time to evaluate nab-paclitaxel in the first-line metastatic setting against gemcitabine (Gemzar) and cisplatin, in cisplatin-ineligible patients, in sequential studies either before or after gemcitabine/cisplatin, or with other chemotherapies or targeted therapy, said Dr. Sridhar of Princess Margaret Hospital in Toronto. A phase II trial (NCT00995488) is currently recruiting patients to evaluate the efficacy of a combination of nab-paclitaxel, carboplatin, and gemcitabine for the first-line treatment of metastatic urothelial cancer.

Standard first-line treatment for metastatic urothelial cancer is cisplatin-based chemotherapy. Despite high response rates of 40%-45%, however, most patients relapse, and median survival is only 12-14 months.

There is currently no approved second-line treatment option for urothelial cancer, the fifth most common cancer in North America, with an estimated 14,000 annual deaths.

In nine previous single-agent second-line trials, pemetrexed achieved the highest response rate of 28%, with a median time to progression of 2.9 months and a median survival of 9.6 months (J. Clin. Oncol. 2006;24:3451-7), she said. In nine combination second-line trials, gemcitabine and paclitaxel together achieved the best response rate of 60% and a median survival of 14.4 months (Cancer 2001;92:2993-8).

The median time to disease progression with nab-paclitaxel was 6.0 months, and the median overall survival was 10.8 months, Dr. Sridhar reported.

Factors associated with improved overall survival were, not surprisingly, a hemoglobin level of at least 100 g/L, a performance status of 1 or less, last chemotherapy at least 5 months before treatment, and achieving disease control, either a partial response or stable disease, with nab-paclitaxel.

Patients in the trial had measurable distant or unresectable local urothelial cancer of mixed histology that had progressed on or within 1 year of platinum-based chemotherapy. They had received no prior taxanes for metastatic disease, had a performance status of 0-2, and had a glomerular filtration rate of more than 40 mL/min.

In all, 48 patients received intravenous nab-paclitaxel 260 mg/m2 every 3 weeks until disease progression or intolerable toxicity occurred. The median number of cycles was six. Dose reductions were required in 33% of patients, mostly because of fatigue or neuropathy, she said.

The most common overall toxicities were alopecia (13%), fatigue (12%), pain (12%), neuropathy (10%), dyspnea (3%), and edema (3%). The most common grade 3 toxicity was pain, which was experienced by 23% of patients, but was not all drug related, Dr. Sridhar said at the symposium, cosponsored by the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology. One patient developed grade 4 fatigue.

Nab-paclitaxel is being investigated in a variety of cancers, and is indicated for the treatment of breast cancer that has failed combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy.

Sunnybrook Health Sciences Centre sponsored the trial in collaboration with Abraxis BioScience. Dr. Sridhar and her coauthors reported no relevant financial disclosures.

ORLANDO – Nanoparticle albumin-bound paclitaxel resulted in an unprecedented single-agent response rate of 32% in metastatic platinum-refractory urothelial cancer in a multicenter phase II study.

Among the 47 patients evaluable for response to nab-paclitaxel (Abraxane), 15 (32%) had a partial response, and 10 (21%) had stable disease, for a disease control rate of 53%.

"This is so far the highest reported single-agent response rate in second-line urothelial cancer," lead author Dr. Srikala S. Sridhar said at the Genitourinary Cancers Symposium. "Time to progression and progression-free survival [are] higher, as is median survival."

The response rate with nab-paclitaxel is in the same range as some second-line combination therapies, with the added benefit of having less toxicity than many of the doublet and triplet combinations, she said.

Based on the results, it may be time to evaluate nab-paclitaxel in the first-line metastatic setting against gemcitabine (Gemzar) and cisplatin, in cisplatin-ineligible patients, in sequential studies either before or after gemcitabine/cisplatin, or with other chemotherapies or targeted therapy, said Dr. Sridhar of Princess Margaret Hospital in Toronto. A phase II trial (NCT00995488) is currently recruiting patients to evaluate the efficacy of a combination of nab-paclitaxel, carboplatin, and gemcitabine for the first-line treatment of metastatic urothelial cancer.

Standard first-line treatment for metastatic urothelial cancer is cisplatin-based chemotherapy. Despite high response rates of 40%-45%, however, most patients relapse, and median survival is only 12-14 months.

There is currently no approved second-line treatment option for urothelial cancer, the fifth most common cancer in North America, with an estimated 14,000 annual deaths.

In nine previous single-agent second-line trials, pemetrexed achieved the highest response rate of 28%, with a median time to progression of 2.9 months and a median survival of 9.6 months (J. Clin. Oncol. 2006;24:3451-7), she said. In nine combination second-line trials, gemcitabine and paclitaxel together achieved the best response rate of 60% and a median survival of 14.4 months (Cancer 2001;92:2993-8).

The median time to disease progression with nab-paclitaxel was 6.0 months, and the median overall survival was 10.8 months, Dr. Sridhar reported.

Factors associated with improved overall survival were, not surprisingly, a hemoglobin level of at least 100 g/L, a performance status of 1 or less, last chemotherapy at least 5 months before treatment, and achieving disease control, either a partial response or stable disease, with nab-paclitaxel.

Patients in the trial had measurable distant or unresectable local urothelial cancer of mixed histology that had progressed on or within 1 year of platinum-based chemotherapy. They had received no prior taxanes for metastatic disease, had a performance status of 0-2, and had a glomerular filtration rate of more than 40 mL/min.

In all, 48 patients received intravenous nab-paclitaxel 260 mg/m2 every 3 weeks until disease progression or intolerable toxicity occurred. The median number of cycles was six. Dose reductions were required in 33% of patients, mostly because of fatigue or neuropathy, she said.

The most common overall toxicities were alopecia (13%), fatigue (12%), pain (12%), neuropathy (10%), dyspnea (3%), and edema (3%). The most common grade 3 toxicity was pain, which was experienced by 23% of patients, but was not all drug related, Dr. Sridhar said at the symposium, cosponsored by the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology. One patient developed grade 4 fatigue.

Nab-paclitaxel is being investigated in a variety of cancers, and is indicated for the treatment of breast cancer that has failed combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy.

Sunnybrook Health Sciences Centre sponsored the trial in collaboration with Abraxis BioScience. Dr. Sridhar and her coauthors reported no relevant financial disclosures.

ORLANDO – Nanoparticle albumin-bound paclitaxel resulted in an unprecedented single-agent response rate of 32% in metastatic platinum-refractory urothelial cancer in a multicenter phase II study.

Among the 47 patients evaluable for response to nab-paclitaxel (Abraxane), 15 (32%) had a partial response, and 10 (21%) had stable disease, for a disease control rate of 53%.

"This is so far the highest reported single-agent response rate in second-line urothelial cancer," lead author Dr. Srikala S. Sridhar said at the Genitourinary Cancers Symposium. "Time to progression and progression-free survival [are] higher, as is median survival."

The response rate with nab-paclitaxel is in the same range as some second-line combination therapies, with the added benefit of having less toxicity than many of the doublet and triplet combinations, she said.

Based on the results, it may be time to evaluate nab-paclitaxel in the first-line metastatic setting against gemcitabine (Gemzar) and cisplatin, in cisplatin-ineligible patients, in sequential studies either before or after gemcitabine/cisplatin, or with other chemotherapies or targeted therapy, said Dr. Sridhar of Princess Margaret Hospital in Toronto. A phase II trial (NCT00995488) is currently recruiting patients to evaluate the efficacy of a combination of nab-paclitaxel, carboplatin, and gemcitabine for the first-line treatment of metastatic urothelial cancer.

Standard first-line treatment for metastatic urothelial cancer is cisplatin-based chemotherapy. Despite high response rates of 40%-45%, however, most patients relapse, and median survival is only 12-14 months.

There is currently no approved second-line treatment option for urothelial cancer, the fifth most common cancer in North America, with an estimated 14,000 annual deaths.

In nine previous single-agent second-line trials, pemetrexed achieved the highest response rate of 28%, with a median time to progression of 2.9 months and a median survival of 9.6 months (J. Clin. Oncol. 2006;24:3451-7), she said. In nine combination second-line trials, gemcitabine and paclitaxel together achieved the best response rate of 60% and a median survival of 14.4 months (Cancer 2001;92:2993-8).

The median time to disease progression with nab-paclitaxel was 6.0 months, and the median overall survival was 10.8 months, Dr. Sridhar reported.

Factors associated with improved overall survival were, not surprisingly, a hemoglobin level of at least 100 g/L, a performance status of 1 or less, last chemotherapy at least 5 months before treatment, and achieving disease control, either a partial response or stable disease, with nab-paclitaxel.

Patients in the trial had measurable distant or unresectable local urothelial cancer of mixed histology that had progressed on or within 1 year of platinum-based chemotherapy. They had received no prior taxanes for metastatic disease, had a performance status of 0-2, and had a glomerular filtration rate of more than 40 mL/min.

In all, 48 patients received intravenous nab-paclitaxel 260 mg/m2 every 3 weeks until disease progression or intolerable toxicity occurred. The median number of cycles was six. Dose reductions were required in 33% of patients, mostly because of fatigue or neuropathy, she said.

The most common overall toxicities were alopecia (13%), fatigue (12%), pain (12%), neuropathy (10%), dyspnea (3%), and edema (3%). The most common grade 3 toxicity was pain, which was experienced by 23% of patients, but was not all drug related, Dr. Sridhar said at the symposium, cosponsored by the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology. One patient developed grade 4 fatigue.

Nab-paclitaxel is being investigated in a variety of cancers, and is indicated for the treatment of breast cancer that has failed combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy.

Sunnybrook Health Sciences Centre sponsored the trial in collaboration with Abraxis BioScience. Dr. Sridhar and her coauthors reported no relevant financial disclosures.

ORLANDO – Periodic breaks from androgen suppression therapy did not impact survival in men with prostate-specific antigen progression after radical therapy for prostate cancer.

In a phase III study involving 1,386 men, median overall survival was 9.1 years with continuous androgen deprivation and 8.8 years with intermittent androgen suppression (P value .009, hazard ratio 1.02), lead author Dr. Laurence Klotz said at the Genitourinary Cancers Symposium. Median follow-up was 6.9 years.

"Based on this study, which is really, I think a pivotal, definitive trial of this question, IAS [intermittent androgen suppression] should be the standard of care for most patients with PSA [prostate-specific antigen] recurrence after radiation, who are initiating androgen deprivation therapy," he said.

The inter-group study, which was stopped early based on the interim analysis, answers the long-standing question of survival for a therapeutic approach that is increasingly popular among clinicians and patients.

Intermittent androgen suppression was first described in a report by Dr. Klotz in 1986 and since then has been the subject of 17 phase II and nine phase III studies. Although previous studies reported favorable results, they were either too small to determine survival non-inferiority or included patients with both metastatic and non-metastatic disease, he said.

The current study included men without metastatic disease who had a rising serum prostate-specific antigen of more than 3 ng/ml and serum testosterone of more than 5 nmol/L at one year after undergoing radiation therapy, either as primary management or post radical prostatectomy. PSA testing was performed every 2 months.

In the randomized multi-center trial, 696 patients received initial flare blockade with an anti-androgen (AA) and therapy with a luteinizing hormone-releasing hormone (LHRH) analog until castrate resistance and 690 patients received initial AA and LHRH for 8 months, at which time therapy was stopped if PSA levels became normal. If PSA rose to more than 10 mg/ml, the 8 months of therapy was repeated. Patients were switched to continuous androgen deprivation at disease progression or with a PSA of more than 10 ng/ml within 2 months of discontinuing therapy.

Dr. Christopher Logothetis, chair of genitourinary medical oncology at MD Anderson Cancer Center in Houston, said in an interview that another trial is unlikely to be conducted and that the current findings make intermittent therapy the preferred treatment. He has been using intermittent androgen suppression for more than 5 years in his patients and said the difference in quality of life is striking for these men.

"I’m not sure that the side effect profile he [Dr. Klotz] described captures the degree of benefit that patients feel when they have a normal testosterone – this general sense of well-being, a sort of equanimity they experience and return to life and engagement," he said. "My own view of life is that the benefits are underestimated."

Significant adverse events were similar between the intermittent androgen suppression and continuous androgen deprivation patients, including erectile dysfunction (86% vs. 88%), libido (79% both groups), urine frequency/urgency (61% vs. 57%), fatigue (59% both groups), myocardial ischemia/infarction (10% vs. 11%), and osteoporotic fracture (4% vs. 3%). The only real difference was in hot flashes, favoring the intermittent androgen suppression arm at 90% vs. 93% (P = .04), said Dr. Klotz, chief of urology, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada

Quality-of-life studies, which will address off-treatment events, will be reported at a future meeting.

The median time to castration resistance was 10 years with continuous androgen deprivation and 9.8 years with intermittent androgen suppression, although a stratified log-rank analysis favored the intermittent arm (P = .024, HR 0.80). This finding may reflect the study design, which was biased toward a longer time of castrate resistance in the intermittent arm because patients off treatment had to be retreated before they could be defined as castrate resistant, he said.

There were 9% more prostate cancer deaths on intermittent androgen suppression and 8% more non-prostate cancer deaths on continuous androgen deprivation. Seven-year disease-specific mortality was 18% in the intermittent androgen suppression arm vs. 15% in the continuous arm (P = .24, HR 1.18).

Dr. Klotz suggested that the increase in non-prostate cancer deaths in the continuous androgen deprivation arm may be related to the metabolic effects of long-term continuous androgen deprivation. The increase in prostate cancer deaths in the intermittent arm "is going to be a matter, I think, for some discussion and controversy," even though it was statistically insignificant and "a very secondary point compared to the observation of no difference in overall survival," he added.

Surprisingly, the average on-treatment time was only 27% on average in the intermittent arm, with men spending a median of 15.4 months on therapy and 37.6 months off therapy. Dr. Klotz pointed out that this contrasts with an on-treatment time of 50% observed in most of the phase II studies.

"This is actually quite reassuring and I think important data that, at least in this scenario, patients tend to stay off treatment for a much longer period of time," he said at the symposium, co-sponsored by the American Society for Clinical Oncology, American Society for Radiation Oncology, and the Society of Urologic Oncology.

Dr. Oliver Sartor, medical director of the Tulane Cancer Center in New Orleans, said the question of survival with intermittent therapy has now been answered, and that it is very reasonable for intermittent therapy to be considered the standard of care in these patients.

"The only caveat is that you do have to monitor this; you just can’t send them out the door and say, ‘I’ll see you in a year,’ " said Dr. Sartor, who has been using intermittent therapy for the past decade in his patients to reduce adverse events. "I will be monitoring, typically, every 2 months."

In an interview, Dr. Klotz described the results as a win-win for patients and may also save them money. Although significantly less costly than many of the newer targeted therapies, a monthly injection costs about $350. He speculated that in treatment-naïve patients, the investigational agent MDV3100 and intermittent androgen deprivation may be a good partnership, but did not recommend this approach with abiraterone acetate should it gain approval this year, as is anticipated.

Of the 1,368 men evaluated, 11% had undergone a prior prostatectomy, and for 78%, it had been at least 3 years since radiation therapy. They had a median age of 74 years, 81% had a performance status of 0, and 23% had a PSA of more than 15 ng/ml when entering the trial, which was sponsored by several research groups including the National Cancer Institute Clinical Trials Group and Southwest Oncology Group.

Dr. Klotz and his co-authors disclosed no conflicts. Dr. Logothetis disclosed consulting for and honoraria and research funding from several drug companies. Dr. Sartor disclosed honoraria from Sanofi-Aventis as well as consulting for and receiving research funding from multiple drug companies.

ORLANDO – Periodic breaks from androgen suppression therapy did not impact survival in men with prostate-specific antigen progression after radical therapy for prostate cancer.

In a phase III study involving 1,386 men, median overall survival was 9.1 years with continuous androgen deprivation and 8.8 years with intermittent androgen suppression (P value .009, hazard ratio 1.02), lead author Dr. Laurence Klotz said at the Genitourinary Cancers Symposium. Median follow-up was 6.9 years.

"Based on this study, which is really, I think a pivotal, definitive trial of this question, IAS [intermittent androgen suppression] should be the standard of care for most patients with PSA [prostate-specific antigen] recurrence after radiation, who are initiating androgen deprivation therapy," he said.

The inter-group study, which was stopped early based on the interim analysis, answers the long-standing question of survival for a therapeutic approach that is increasingly popular among clinicians and patients.

Intermittent androgen suppression was first described in a report by Dr. Klotz in 1986 and since then has been the subject of 17 phase II and nine phase III studies. Although previous studies reported favorable results, they were either too small to determine survival non-inferiority or included patients with both metastatic and non-metastatic disease, he said.

The current study included men without metastatic disease who had a rising serum prostate-specific antigen of more than 3 ng/ml and serum testosterone of more than 5 nmol/L at one year after undergoing radiation therapy, either as primary management or post radical prostatectomy. PSA testing was performed every 2 months.

In the randomized multi-center trial, 696 patients received initial flare blockade with an anti-androgen (AA) and therapy with a luteinizing hormone-releasing hormone (LHRH) analog until castrate resistance and 690 patients received initial AA and LHRH for 8 months, at which time therapy was stopped if PSA levels became normal. If PSA rose to more than 10 mg/ml, the 8 months of therapy was repeated. Patients were switched to continuous androgen deprivation at disease progression or with a PSA of more than 10 ng/ml within 2 months of discontinuing therapy.

Dr. Christopher Logothetis, chair of genitourinary medical oncology at MD Anderson Cancer Center in Houston, said in an interview that another trial is unlikely to be conducted and that the current findings make intermittent therapy the preferred treatment. He has been using intermittent androgen suppression for more than 5 years in his patients and said the difference in quality of life is striking for these men.

"I’m not sure that the side effect profile he [Dr. Klotz] described captures the degree of benefit that patients feel when they have a normal testosterone – this general sense of well-being, a sort of equanimity they experience and return to life and engagement," he said. "My own view of life is that the benefits are underestimated."

Significant adverse events were similar between the intermittent androgen suppression and continuous androgen deprivation patients, including erectile dysfunction (86% vs. 88%), libido (79% both groups), urine frequency/urgency (61% vs. 57%), fatigue (59% both groups), myocardial ischemia/infarction (10% vs. 11%), and osteoporotic fracture (4% vs. 3%). The only real difference was in hot flashes, favoring the intermittent androgen suppression arm at 90% vs. 93% (P = .04), said Dr. Klotz, chief of urology, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada

Quality-of-life studies, which will address off-treatment events, will be reported at a future meeting.

The median time to castration resistance was 10 years with continuous androgen deprivation and 9.8 years with intermittent androgen suppression, although a stratified log-rank analysis favored the intermittent arm (P = .024, HR 0.80). This finding may reflect the study design, which was biased toward a longer time of castrate resistance in the intermittent arm because patients off treatment had to be retreated before they could be defined as castrate resistant, he said.

There were 9% more prostate cancer deaths on intermittent androgen suppression and 8% more non-prostate cancer deaths on continuous androgen deprivation. Seven-year disease-specific mortality was 18% in the intermittent androgen suppression arm vs. 15% in the continuous arm (P = .24, HR 1.18).

Dr. Klotz suggested that the increase in non-prostate cancer deaths in the continuous androgen deprivation arm may be related to the metabolic effects of long-term continuous androgen deprivation. The increase in prostate cancer deaths in the intermittent arm "is going to be a matter, I think, for some discussion and controversy," even though it was statistically insignificant and "a very secondary point compared to the observation of no difference in overall survival," he added.

Surprisingly, the average on-treatment time was only 27% on average in the intermittent arm, with men spending a median of 15.4 months on therapy and 37.6 months off therapy. Dr. Klotz pointed out that this contrasts with an on-treatment time of 50% observed in most of the phase II studies.

"This is actually quite reassuring and I think important data that, at least in this scenario, patients tend to stay off treatment for a much longer period of time," he said at the symposium, co-sponsored by the American Society for Clinical Oncology, American Society for Radiation Oncology, and the Society of Urologic Oncology.

Dr. Oliver Sartor, medical director of the Tulane Cancer Center in New Orleans, said the question of survival with intermittent therapy has now been answered, and that it is very reasonable for intermittent therapy to be considered the standard of care in these patients.

"The only caveat is that you do have to monitor this; you just can’t send them out the door and say, ‘I’ll see you in a year,’ " said Dr. Sartor, who has been using intermittent therapy for the past decade in his patients to reduce adverse events. "I will be monitoring, typically, every 2 months."

In an interview, Dr. Klotz described the results as a win-win for patients and may also save them money. Although significantly less costly than many of the newer targeted therapies, a monthly injection costs about $350. He speculated that in treatment-naïve patients, the investigational agent MDV3100 and intermittent androgen deprivation may be a good partnership, but did not recommend this approach with abiraterone acetate should it gain approval this year, as is anticipated.

Of the 1,368 men evaluated, 11% had undergone a prior prostatectomy, and for 78%, it had been at least 3 years since radiation therapy. They had a median age of 74 years, 81% had a performance status of 0, and 23% had a PSA of more than 15 ng/ml when entering the trial, which was sponsored by several research groups including the National Cancer Institute Clinical Trials Group and Southwest Oncology Group.

Dr. Klotz and his co-authors disclosed no conflicts. Dr. Logothetis disclosed consulting for and honoraria and research funding from several drug companies. Dr. Sartor disclosed honoraria from Sanofi-Aventis as well as consulting for and receiving research funding from multiple drug companies.

ORLANDO – Periodic breaks from androgen suppression therapy did not impact survival in men with prostate-specific antigen progression after radical therapy for prostate cancer.

In a phase III study involving 1,386 men, median overall survival was 9.1 years with continuous androgen deprivation and 8.8 years with intermittent androgen suppression (P value .009, hazard ratio 1.02), lead author Dr. Laurence Klotz said at the Genitourinary Cancers Symposium. Median follow-up was 6.9 years.

"Based on this study, which is really, I think a pivotal, definitive trial of this question, IAS [intermittent androgen suppression] should be the standard of care for most patients with PSA [prostate-specific antigen] recurrence after radiation, who are initiating androgen deprivation therapy," he said.

The inter-group study, which was stopped early based on the interim analysis, answers the long-standing question of survival for a therapeutic approach that is increasingly popular among clinicians and patients.

Intermittent androgen suppression was first described in a report by Dr. Klotz in 1986 and since then has been the subject of 17 phase II and nine phase III studies. Although previous studies reported favorable results, they were either too small to determine survival non-inferiority or included patients with both metastatic and non-metastatic disease, he said.

The current study included men without metastatic disease who had a rising serum prostate-specific antigen of more than 3 ng/ml and serum testosterone of more than 5 nmol/L at one year after undergoing radiation therapy, either as primary management or post radical prostatectomy. PSA testing was performed every 2 months.

In the randomized multi-center trial, 696 patients received initial flare blockade with an anti-androgen (AA) and therapy with a luteinizing hormone-releasing hormone (LHRH) analog until castrate resistance and 690 patients received initial AA and LHRH for 8 months, at which time therapy was stopped if PSA levels became normal. If PSA rose to more than 10 mg/ml, the 8 months of therapy was repeated. Patients were switched to continuous androgen deprivation at disease progression or with a PSA of more than 10 ng/ml within 2 months of discontinuing therapy.

Dr. Christopher Logothetis, chair of genitourinary medical oncology at MD Anderson Cancer Center in Houston, said in an interview that another trial is unlikely to be conducted and that the current findings make intermittent therapy the preferred treatment. He has been using intermittent androgen suppression for more than 5 years in his patients and said the difference in quality of life is striking for these men.

"I’m not sure that the side effect profile he [Dr. Klotz] described captures the degree of benefit that patients feel when they have a normal testosterone – this general sense of well-being, a sort of equanimity they experience and return to life and engagement," he said. "My own view of life is that the benefits are underestimated."

Significant adverse events were similar between the intermittent androgen suppression and continuous androgen deprivation patients, including erectile dysfunction (86% vs. 88%), libido (79% both groups), urine frequency/urgency (61% vs. 57%), fatigue (59% both groups), myocardial ischemia/infarction (10% vs. 11%), and osteoporotic fracture (4% vs. 3%). The only real difference was in hot flashes, favoring the intermittent androgen suppression arm at 90% vs. 93% (P = .04), said Dr. Klotz, chief of urology, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada

Quality-of-life studies, which will address off-treatment events, will be reported at a future meeting.

The median time to castration resistance was 10 years with continuous androgen deprivation and 9.8 years with intermittent androgen suppression, although a stratified log-rank analysis favored the intermittent arm (P = .024, HR 0.80). This finding may reflect the study design, which was biased toward a longer time of castrate resistance in the intermittent arm because patients off treatment had to be retreated before they could be defined as castrate resistant, he said.

There were 9% more prostate cancer deaths on intermittent androgen suppression and 8% more non-prostate cancer deaths on continuous androgen deprivation. Seven-year disease-specific mortality was 18% in the intermittent androgen suppression arm vs. 15% in the continuous arm (P = .24, HR 1.18).

Dr. Klotz suggested that the increase in non-prostate cancer deaths in the continuous androgen deprivation arm may be related to the metabolic effects of long-term continuous androgen deprivation. The increase in prostate cancer deaths in the intermittent arm "is going to be a matter, I think, for some discussion and controversy," even though it was statistically insignificant and "a very secondary point compared to the observation of no difference in overall survival," he added.

Surprisingly, the average on-treatment time was only 27% on average in the intermittent arm, with men spending a median of 15.4 months on therapy and 37.6 months off therapy. Dr. Klotz pointed out that this contrasts with an on-treatment time of 50% observed in most of the phase II studies.

"This is actually quite reassuring and I think important data that, at least in this scenario, patients tend to stay off treatment for a much longer period of time," he said at the symposium, co-sponsored by the American Society for Clinical Oncology, American Society for Radiation Oncology, and the Society of Urologic Oncology.

Dr. Oliver Sartor, medical director of the Tulane Cancer Center in New Orleans, said the question of survival with intermittent therapy has now been answered, and that it is very reasonable for intermittent therapy to be considered the standard of care in these patients.

"The only caveat is that you do have to monitor this; you just can’t send them out the door and say, ‘I’ll see you in a year,’ " said Dr. Sartor, who has been using intermittent therapy for the past decade in his patients to reduce adverse events. "I will be monitoring, typically, every 2 months."

In an interview, Dr. Klotz described the results as a win-win for patients and may also save them money. Although significantly less costly than many of the newer targeted therapies, a monthly injection costs about $350. He speculated that in treatment-naïve patients, the investigational agent MDV3100 and intermittent androgen deprivation may be a good partnership, but did not recommend this approach with abiraterone acetate should it gain approval this year, as is anticipated.

Of the 1,368 men evaluated, 11% had undergone a prior prostatectomy, and for 78%, it had been at least 3 years since radiation therapy. They had a median age of 74 years, 81% had a performance status of 0, and 23% had a PSA of more than 15 ng/ml when entering the trial, which was sponsored by several research groups including the National Cancer Institute Clinical Trials Group and Southwest Oncology Group.

Dr. Klotz and his co-authors disclosed no conflicts. Dr. Logothetis disclosed consulting for and honoraria and research funding from several drug companies. Dr. Sartor disclosed honoraria from Sanofi-Aventis as well as consulting for and receiving research funding from multiple drug companies.

Use of robotic prostatectomy has mushroomed in the United States, but new data suggest it is best left in the hands of expert surgeons.

A multicenter analysis of 3,794 cases of robotic-assisted laparoscopic radical prostatectomy (RALP) performed by three experienced surgeons found that at least 1,500-1,600 cases were needed to achieve a positive surgical margin (PSM) rate of less than 10%, which is widely accepted in the surgical literature as a sign of excellence.

"We recommend that this operation should not be done by all urologists in small community hospitals, but should be focused and concentrated into those high-volume centers of excellence where the operation can be done by surgeons doing a large number of cases, very frequently, in order that they can achieve the best possible cancer-control results for their patients," lead author Dr. Prasanna Sooriakumaran said during a Feb. 15 press briefing for a symposium on genitourinary cancers.

Of the roughly 90,000 radical prostatectomies performed each year in the United States to treat prostate cancer, more than 70,000 are robot assisted and more than 70% of these are performed by surgeons who do fewer than 100 cases of RALP per year, he said.

The growing popularity of RALP was stoked by reports that the learning curve with regard to safety is around 25-40 cases. There is no good evidence in the literature, however, as to how long it takes to achieve expert level or optimal results for the patient, said Dr. Sooriakumaran, a visiting fellow in urology at the Weill Cornell Medical College in New York.

The researchers divided the cases based on surgeon experience, beginning at fewer than 50 cases and progressing to more than 1,000 cases performed. The median preoperative prostate-specific antigen level (range 4.7-5.4 ng/mL) and median age at surgery (range 60-61 years) remained relatively constant with increasing surgeon experience.

As surgeon experience increased, however, the number of patients with high-grade cancer, defined by a Gleason score of more than 7, decreased from 8.2% to 5.6%, and the number of patients with extracapsular invasion or pT3 disease decreased from 27% to 16%, suggesting that patients should have better results since the cases were getting more curable with time, Dr. Sooriakumaran said.

PSM rates for all patients start off at about 20% when surgeons begin learning the procedure, and it takes about 1,500-1,600 cases for margin rates to reach less than 10%. Notably, margin rates continue to fall beyond 1,600 cases, suggesting that the learning curve continues, even when PSM rates fall below 10%, he said.

When only patients with pT3 disease were evaluated, the learning curve starts to plateau after 1,000-1,500 cases, which is to be expected because these patients have prostate cancer outside the prostate, and therefore an operation to simply remove the prostate is more likely to leave cancer cells behind, Dr. Sooriakumaran said.

Operating times for the three surgeons started off at 3 hours and plateaued at around 2 hours after 750-1,000 cases, regardless of whether patients had extracapsular extension or not.

When asked how surgeons at community hospitals should gain experience if the procedure is limited to high-volume centers, Dr. Sooriakumaran said there has to be a balance and likened the situation to what is occurring with laparoscopic radical prostatectomy, which was popularized in the United States but was found to be a difficult operation to perform safely and is now done by only a few expert surgeons.

Press briefing moderator Dr. Nicholas Vogelzang, who is with US Oncology, said this scenario is already playing out in Las Vegas, where internal discussions among 40-45 urologists have delineated the use of RALP to 4 or 5 who will become experts in the procedure.

When asked if it was fair to extrapolate the experiences of three surgeons to all surgeons with regard to RALP proficiency, Dr. Sooriakumaran said the three physicians studied were all experienced, high-volume surgeons at centers in the United States and Europe.

The study will be formally presented at the symposium, which is sponsored by the American Society of Clinical Oncology, American Society for Radiation Oncology, and Society of Urologic Oncology.

Dr. Sooriakumaran disclosed no conflicts. Coauthor Dr. Ashutosh Tewari disclosed research funding from Intuitive Surgical Inc. Dr. Vogelzang disclosed financial relationships with multiple pharmaceutical companies.

Use of robotic prostatectomy has mushroomed in the United States, but new data suggest it is best left in the hands of expert surgeons.

A multicenter analysis of 3,794 cases of robotic-assisted laparoscopic radical prostatectomy (RALP) performed by three experienced surgeons found that at least 1,500-1,600 cases were needed to achieve a positive surgical margin (PSM) rate of less than 10%, which is widely accepted in the surgical literature as a sign of excellence.

"We recommend that this operation should not be done by all urologists in small community hospitals, but should be focused and concentrated into those high-volume centers of excellence where the operation can be done by surgeons doing a large number of cases, very frequently, in order that they can achieve the best possible cancer-control results for their patients," lead author Dr. Prasanna Sooriakumaran said during a Feb. 15 press briefing for a symposium on genitourinary cancers.

Of the roughly 90,000 radical prostatectomies performed each year in the United States to treat prostate cancer, more than 70,000 are robot assisted and more than 70% of these are performed by surgeons who do fewer than 100 cases of RALP per year, he said.

The growing popularity of RALP was stoked by reports that the learning curve with regard to safety is around 25-40 cases. There is no good evidence in the literature, however, as to how long it takes to achieve expert level or optimal results for the patient, said Dr. Sooriakumaran, a visiting fellow in urology at the Weill Cornell Medical College in New York.

The researchers divided the cases based on surgeon experience, beginning at fewer than 50 cases and progressing to more than 1,000 cases performed. The median preoperative prostate-specific antigen level (range 4.7-5.4 ng/mL) and median age at surgery (range 60-61 years) remained relatively constant with increasing surgeon experience.

As surgeon experience increased, however, the number of patients with high-grade cancer, defined by a Gleason score of more than 7, decreased from 8.2% to 5.6%, and the number of patients with extracapsular invasion or pT3 disease decreased from 27% to 16%, suggesting that patients should have better results since the cases were getting more curable with time, Dr. Sooriakumaran said.

PSM rates for all patients start off at about 20% when surgeons begin learning the procedure, and it takes about 1,500-1,600 cases for margin rates to reach less than 10%. Notably, margin rates continue to fall beyond 1,600 cases, suggesting that the learning curve continues, even when PSM rates fall below 10%, he said.

When only patients with pT3 disease were evaluated, the learning curve starts to plateau after 1,000-1,500 cases, which is to be expected because these patients have prostate cancer outside the prostate, and therefore an operation to simply remove the prostate is more likely to leave cancer cells behind, Dr. Sooriakumaran said.

Operating times for the three surgeons started off at 3 hours and plateaued at around 2 hours after 750-1,000 cases, regardless of whether patients had extracapsular extension or not.

When asked how surgeons at community hospitals should gain experience if the procedure is limited to high-volume centers, Dr. Sooriakumaran said there has to be a balance and likened the situation to what is occurring with laparoscopic radical prostatectomy, which was popularized in the United States but was found to be a difficult operation to perform safely and is now done by only a few expert surgeons.

Press briefing moderator Dr. Nicholas Vogelzang, who is with US Oncology, said this scenario is already playing out in Las Vegas, where internal discussions among 40-45 urologists have delineated the use of RALP to 4 or 5 who will become experts in the procedure.

When asked if it was fair to extrapolate the experiences of three surgeons to all surgeons with regard to RALP proficiency, Dr. Sooriakumaran said the three physicians studied were all experienced, high-volume surgeons at centers in the United States and Europe.

The study will be formally presented at the symposium, which is sponsored by the American Society of Clinical Oncology, American Society for Radiation Oncology, and Society of Urologic Oncology.

Dr. Sooriakumaran disclosed no conflicts. Coauthor Dr. Ashutosh Tewari disclosed research funding from Intuitive Surgical Inc. Dr. Vogelzang disclosed financial relationships with multiple pharmaceutical companies.

Use of robotic prostatectomy has mushroomed in the United States, but new data suggest it is best left in the hands of expert surgeons.

A multicenter analysis of 3,794 cases of robotic-assisted laparoscopic radical prostatectomy (RALP) performed by three experienced surgeons found that at least 1,500-1,600 cases were needed to achieve a positive surgical margin (PSM) rate of less than 10%, which is widely accepted in the surgical literature as a sign of excellence.

"We recommend that this operation should not be done by all urologists in small community hospitals, but should be focused and concentrated into those high-volume centers of excellence where the operation can be done by surgeons doing a large number of cases, very frequently, in order that they can achieve the best possible cancer-control results for their patients," lead author Dr. Prasanna Sooriakumaran said during a Feb. 15 press briefing for a symposium on genitourinary cancers.

Of the roughly 90,000 radical prostatectomies performed each year in the United States to treat prostate cancer, more than 70,000 are robot assisted and more than 70% of these are performed by surgeons who do fewer than 100 cases of RALP per year, he said.

The growing popularity of RALP was stoked by reports that the learning curve with regard to safety is around 25-40 cases. There is no good evidence in the literature, however, as to how long it takes to achieve expert level or optimal results for the patient, said Dr. Sooriakumaran, a visiting fellow in urology at the Weill Cornell Medical College in New York.

The researchers divided the cases based on surgeon experience, beginning at fewer than 50 cases and progressing to more than 1,000 cases performed. The median preoperative prostate-specific antigen level (range 4.7-5.4 ng/mL) and median age at surgery (range 60-61 years) remained relatively constant with increasing surgeon experience.

As surgeon experience increased, however, the number of patients with high-grade cancer, defined by a Gleason score of more than 7, decreased from 8.2% to 5.6%, and the number of patients with extracapsular invasion or pT3 disease decreased from 27% to 16%, suggesting that patients should have better results since the cases were getting more curable with time, Dr. Sooriakumaran said.

PSM rates for all patients start off at about 20% when surgeons begin learning the procedure, and it takes about 1,500-1,600 cases for margin rates to reach less than 10%. Notably, margin rates continue to fall beyond 1,600 cases, suggesting that the learning curve continues, even when PSM rates fall below 10%, he said.

When only patients with pT3 disease were evaluated, the learning curve starts to plateau after 1,000-1,500 cases, which is to be expected because these patients have prostate cancer outside the prostate, and therefore an operation to simply remove the prostate is more likely to leave cancer cells behind, Dr. Sooriakumaran said.

Operating times for the three surgeons started off at 3 hours and plateaued at around 2 hours after 750-1,000 cases, regardless of whether patients had extracapsular extension or not.

When asked how surgeons at community hospitals should gain experience if the procedure is limited to high-volume centers, Dr. Sooriakumaran said there has to be a balance and likened the situation to what is occurring with laparoscopic radical prostatectomy, which was popularized in the United States but was found to be a difficult operation to perform safely and is now done by only a few expert surgeons.

Press briefing moderator Dr. Nicholas Vogelzang, who is with US Oncology, said this scenario is already playing out in Las Vegas, where internal discussions among 40-45 urologists have delineated the use of RALP to 4 or 5 who will become experts in the procedure.

When asked if it was fair to extrapolate the experiences of three surgeons to all surgeons with regard to RALP proficiency, Dr. Sooriakumaran said the three physicians studied were all experienced, high-volume surgeons at centers in the United States and Europe.

The study will be formally presented at the symposium, which is sponsored by the American Society of Clinical Oncology, American Society for Radiation Oncology, and Society of Urologic Oncology.

Dr. Sooriakumaran disclosed no conflicts. Coauthor Dr. Ashutosh Tewari disclosed research funding from Intuitive Surgical Inc. Dr. Vogelzang disclosed financial relationships with multiple pharmaceutical companies.

Use of robotic prostatectomy has mushroomed in the United States, but new data suggest it is best left in the hands of expert surgeons.

A multicenter analysis of 3,794 cases of robotic-assisted laparoscopic radical prostatectomy (RALP) performed by three experienced surgeons found that at least 1,500-1,600 cases were needed to achieve a positive surgical margin (PSM) rate of less than 10%, which is widely accepted in the surgical literature as a sign of excellence.

"We recommend that this operation should not be done by all urologists in small community hospitals, but should be focused and concentrated into those high-volume centers of excellence where the operation can be done by surgeons doing a large number of cases, very frequently, in order that they can achieve the best possible cancer-control results for their patients," lead author Dr. Prasanna Sooriakumaran said during a Feb. 15 press briefing for a symposium on genitourinary cancers.

Of the roughly 90,000 radical prostatectomies performed each year in the United States to treat prostate cancer, more than 70,000 are robot assisted and more than 70% of these are performed by surgeons who do fewer than 100 cases of RALP per year, he said.

The growing popularity of RALP was stoked by reports that the learning curve with regard to safety is around 25-40 cases. There is no good evidence in the literature, however, as to how long it takes to achieve expert level or optimal results for the patient, said Dr. Sooriakumaran, a visiting fellow in urology at the Weill Cornell Medical College in New York.

The researchers divided the cases based on surgeon experience, beginning at fewer than 50 cases and progressing to more than 1,000 cases performed. The median preoperative prostate-specific antigen level (range 4.7-5.4 ng/mL) and median age at surgery (range 60-61 years) remained relatively constant with increasing surgeon experience.

As surgeon experience increased, however, the number of patients with high-grade cancer, defined by a Gleason score of more than 7, decreased from 8.2% to 5.6%, and the number of patients with extracapsular invasion or pT3 disease decreased from 27% to 16%, suggesting that patients should have better results since the cases were getting more curable with time, Dr. Sooriakumaran said.

PSM rates for all patients start off at about 20% when surgeons begin learning the procedure, and it takes about 1,500-1,600 cases for margin rates to reach less than 10%. Notably, margin rates continue to fall beyond 1,600 cases, suggesting that the learning curve continues, even when PSM rates fall below 10%, he said.

When only patients with pT3 disease were evaluated, the learning curve starts to plateau after 1,000-1,500 cases, which is to be expected because these patients have prostate cancer outside the prostate, and therefore an operation to simply remove the prostate is more likely to leave cancer cells behind, Dr. Sooriakumaran said.

Operating times for the three surgeons started off at 3 hours and plateaued at around 2 hours after 750-1,000 cases, regardless of whether patients had extracapsular extension or not.

When asked how surgeons at community hospitals should gain experience if the procedure is limited to high-volume centers, Dr. Sooriakumaran said there has to be a balance and likened the situation to what is occurring with laparoscopic radical prostatectomy, which was popularized in the United States but was found to be a difficult operation to perform safely and is now done by only a few expert surgeons.

Press briefing moderator Dr. Nicholas Vogelzang, who is with US Oncology, said this scenario is already playing out in Las Vegas, where internal discussions among 40-45 urologists have delineated the use of RALP to 4 or 5 who will become experts in the procedure.

When asked if it was fair to extrapolate the experiences of three surgeons to all surgeons with regard to RALP proficiency, Dr. Sooriakumaran said the three physicians studied were all experienced, high-volume surgeons at centers in the United States and Europe.

The study will be formally presented at the symposium, which is sponsored by the American Society of Clinical Oncology, American Society for Radiation Oncology, and Society of Urologic Oncology.

Dr. Sooriakumaran disclosed no conflicts. Coauthor Dr. Ashutosh Tewari disclosed research funding from Intuitive Surgical Inc. Dr. Vogelzang disclosed financial relationships with multiple pharmaceutical companies.

Use of robotic prostatectomy has mushroomed in the United States, but new data suggest it is best left in the hands of expert surgeons.

A multicenter analysis of 3,794 cases of robotic-assisted laparoscopic radical prostatectomy (RALP) performed by three experienced surgeons found that at least 1,500-1,600 cases were needed to achieve a positive surgical margin (PSM) rate of less than 10%, which is widely accepted in the surgical literature as a sign of excellence.

"We recommend that this operation should not be done by all urologists in small community hospitals, but should be focused and concentrated into those high-volume centers of excellence where the operation can be done by surgeons doing a large number of cases, very frequently, in order that they can achieve the best possible cancer-control results for their patients," lead author Dr. Prasanna Sooriakumaran said during a Feb. 15 press briefing for a symposium on genitourinary cancers.

Of the roughly 90,000 radical prostatectomies performed each year in the United States to treat prostate cancer, more than 70,000 are robot assisted and more than 70% of these are performed by surgeons who do fewer than 100 cases of RALP per year, he said.

The growing popularity of RALP was stoked by reports that the learning curve with regard to safety is around 25-40 cases. There is no good evidence in the literature, however, as to how long it takes to achieve expert level or optimal results for the patient, said Dr. Sooriakumaran, a visiting fellow in urology at the Weill Cornell Medical College in New York.

The researchers divided the cases based on surgeon experience, beginning at fewer than 50 cases and progressing to more than 1,000 cases performed. The median preoperative prostate-specific antigen level (range 4.7-5.4 ng/mL) and median age at surgery (range 60-61 years) remained relatively constant with increasing surgeon experience.

As surgeon experience increased, however, the number of patients with high-grade cancer, defined by a Gleason score of more than 7, decreased from 8.2% to 5.6%, and the number of patients with extracapsular invasion or pT3 disease decreased from 27% to 16%, suggesting that patients should have better results since the cases were getting more curable with time, Dr. Sooriakumaran said.

PSM rates for all patients start off at about 20% when surgeons begin learning the procedure, and it takes about 1,500-1,600 cases for margin rates to reach less than 10%. Notably, margin rates continue to fall beyond 1,600 cases, suggesting that the learning curve continues, even when PSM rates fall below 10%, he said.

When only patients with pT3 disease were evaluated, the learning curve starts to plateau after 1,000-1,500 cases, which is to be expected because these patients have prostate cancer outside the prostate, and therefore an operation to simply remove the prostate is more likely to leave cancer cells behind, Dr. Sooriakumaran said.

Operating times for the three surgeons started off at 3 hours and plateaued at around 2 hours after 750-1,000 cases, regardless of whether patients had extracapsular extension or not.

When asked how surgeons at community hospitals should gain experience if the procedure is limited to high-volume centers, Dr. Sooriakumaran said there has to be a balance and likened the situation to what is occurring with laparoscopic radical prostatectomy, which was popularized in the United States but was found to be a difficult operation to perform safely and is now done by only a few expert surgeons.

Press briefing moderator Dr. Nicholas Vogelzang, who is with US Oncology, said this scenario is already playing out in Las Vegas, where internal discussions among 40-45 urologists have delineated the use of RALP to 4 or 5 who will become experts in the procedure.

When asked if it was fair to extrapolate the experiences of three surgeons to all surgeons with regard to RALP proficiency, Dr. Sooriakumaran said the three physicians studied were all experienced, high-volume surgeons at centers in the United States and Europe.

The study will be formally presented at the symposium, which is sponsored by the American Society of Clinical Oncology, American Society for Radiation Oncology, and Society of Urologic Oncology.

Dr. Sooriakumaran disclosed no conflicts. Coauthor Dr. Ashutosh Tewari disclosed research funding from Intuitive Surgical Inc. Dr. Vogelzang disclosed financial relationships with multiple pharmaceutical companies.

Use of robotic prostatectomy has mushroomed in the United States, but new data suggest it is best left in the hands of expert surgeons.

A multicenter analysis of 3,794 cases of robotic-assisted laparoscopic radical prostatectomy (RALP) performed by three experienced surgeons found that at least 1,500-1,600 cases were needed to achieve a positive surgical margin (PSM) rate of less than 10%, which is widely accepted in the surgical literature as a sign of excellence.

"We recommend that this operation should not be done by all urologists in small community hospitals, but should be focused and concentrated into those high-volume centers of excellence where the operation can be done by surgeons doing a large number of cases, very frequently, in order that they can achieve the best possible cancer-control results for their patients," lead author Dr. Prasanna Sooriakumaran said during a Feb. 15 press briefing for a symposium on genitourinary cancers.

Of the roughly 90,000 radical prostatectomies performed each year in the United States to treat prostate cancer, more than 70,000 are robot assisted and more than 70% of these are performed by surgeons who do fewer than 100 cases of RALP per year, he said.

The growing popularity of RALP was stoked by reports that the learning curve with regard to safety is around 25-40 cases. There is no good evidence in the literature, however, as to how long it takes to achieve expert level or optimal results for the patient, said Dr. Sooriakumaran, a visiting fellow in urology at the Weill Cornell Medical College in New York.

The researchers divided the cases based on surgeon experience, beginning at fewer than 50 cases and progressing to more than 1,000 cases performed. The median preoperative prostate-specific antigen level (range 4.7-5.4 ng/mL) and median age at surgery (range 60-61 years) remained relatively constant with increasing surgeon experience.

As surgeon experience increased, however, the number of patients with high-grade cancer, defined by a Gleason score of more than 7, decreased from 8.2% to 5.6%, and the number of patients with extracapsular invasion or pT3 disease decreased from 27% to 16%, suggesting that patients should have better results since the cases were getting more curable with time, Dr. Sooriakumaran said.

PSM rates for all patients start off at about 20% when surgeons begin learning the procedure, and it takes about 1,500-1,600 cases for margin rates to reach less than 10%. Notably, margin rates continue to fall beyond 1,600 cases, suggesting that the learning curve continues, even when PSM rates fall below 10%, he said.

When only patients with pT3 disease were evaluated, the learning curve starts to plateau after 1,000-1,500 cases, which is to be expected because these patients have prostate cancer outside the prostate, and therefore an operation to simply remove the prostate is more likely to leave cancer cells behind, Dr. Sooriakumaran said.

Operating times for the three surgeons started off at 3 hours and plateaued at around 2 hours after 750-1,000 cases, regardless of whether patients had extracapsular extension or not.

When asked how surgeons at community hospitals should gain experience if the procedure is limited to high-volume centers, Dr. Sooriakumaran said there has to be a balance and likened the situation to what is occurring with laparoscopic radical prostatectomy, which was popularized in the United States but was found to be a difficult operation to perform safely and is now done by only a few expert surgeons.

Press briefing moderator Dr. Nicholas Vogelzang, who is with US Oncology, said this scenario is already playing out in Las Vegas, where internal discussions among 40-45 urologists have delineated the use of RALP to 4 or 5 who will become experts in the procedure.

When asked if it was fair to extrapolate the experiences of three surgeons to all surgeons with regard to RALP proficiency, Dr. Sooriakumaran said the three physicians studied were all experienced, high-volume surgeons at centers in the United States and Europe.

The study will be formally presented at the symposium, which is sponsored by the American Society of Clinical Oncology, American Society for Radiation Oncology, and Society of Urologic Oncology.

Dr. Sooriakumaran disclosed no conflicts. Coauthor Dr. Ashutosh Tewari disclosed research funding from Intuitive Surgical Inc. Dr. Vogelzang disclosed financial relationships with multiple pharmaceutical companies.