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Small renal masses: Toward more rational treatment
Opinion about treatment of mall renal masses has changed considerably in the past 2 decades.
Traditionally, the most common treatment was surgical removal of the whole kidney, ie, radical nephrectomy. However, recent studies have shown that many patients who undergo radical nephrectomy develop chronic kidney disease. Furthermore, radical nephrectomy often constitutes over-treatment, as many of these lesions are benign or, if malignant, would follow an indolent course if left alone.
Now that we better understand the biology of small renal masses and are more aware of the morbidity and mortality related to chronic kidney disease, we try to avoid radical nephrectomy whenever possible, favoring nephron-sparing approaches instead.
In this article, we review the current clinical management of small renal masses.
SMALL RENAL MASSES ARE A HETEROGENEOUS GROUP
Small renal masses are defined as solid renal tumors that enhance on computed tomography (CT) and magnetic resonance imaging (MRI) and are suspected of being renal cell carcinomas. They are generally low-stage and relatively small (< 4 cm in diameter) at presentation. Most are now discovered incidentally on CT or MRI done for various abdominal symptoms. From 20,000 to 30,000 new cases are diagnosed each year in the United States, and the rate is increasing by 3% to 4% per year as the use of CT and MRI increases.1,2
With more small renal masses being detected incidentally, renal cell carcinoma has been going through a stage and size migration—ie, more of these tumors are being discovered in clinical stage T1 (ie, confined to the kidney and measuring less than 7 cm) than in the past. Currently, clinical T1 renal tumors account for 48% to 66% of cases.3
This indicates that the disease is being detected and treated earlier in its course than in the past. However, cancer-specific deaths from renal cell carcinoma have not declined, suggesting that for many of these patients, our traditional practice of aggressive surgical management with radical nephrectomy may not be warranted.4
Small renal masses vary in biologic aggressiveness
Recent large surgical series indicate that up to 20% of small renal masses are benign, 55% to 60% are indolent renal cell carcinomas, and only 20% to 25% have potentially aggressive features, defined by high nuclear grade or locally invasive characteristics.5–7
A relatively strong predictor of the aggressiveness of renal tumors is their size, which directly correlates with the risk of malignant pathology. Of lesions smaller than 1.0 cm, 38% to 46% are benign, dramatically decreasing to 6.3% to 7.1% for lesions larger than 7.0 cm.5 Each 1.0-cm increase in tumor diameter correlates with a 16% increase in the risk of malignancy.8
Our knowledge of the natural history of small renal masses is limited, being based on small, retrospective series. In these studies, when small renal masses were followed over time, relatively few progressed (ie, metastasized), and there have been no documented reports of disease progression in the absence of demonstrable tumor growth, suggesting a predominance of nonaggressive phenotypes.9
In light of these observations, patients with small renal masses should be carefully evaluated to determine if they are candidates for active surveillance as opposed to more aggressive treatment, ie, surgery or thermal ablation.
CT AND MRI ARE THE PREFERRED DIAGNOSTIC STUDIES
In the past, most patients with renal tumors presented with gross hematuria, flank pain, or a palpable abdominal mass. These presentations are now uncommon, as most cases are asymptomatic and are diagnosed incidentally. In a series of 349 small renal masses, microhematuria was found in only 8 cases.10
Systemic manifestations or paraneoplastic syndromes such as hypercalcemia or hypertension are more common in patients with metastatic renal cell carcinoma than in those with localized tumors. It was because of these varied clinical presentations that renal cell carcinoma was previously known as the “internist’s tumor”; however, small renal masses are better termed the “radiologist’s tumor.”11
High-quality axial imaging with CT or MRI is preferred for evaluating renal cortical neoplasms. Enhancement on CT or MRI is the characteristic finding of a renal lesion that should be suspected of being renal cell carcinoma (Figure 1). Triple-phase CT is ideal, with images taken before contrast is given, immediately after contrast (the early vascular phase), and later (the delayed phase). Alternatively, MRI can be used in patients who are allergic to intravenous contrast or who have moderate renal dysfunction.
Renal tumors with enhancement of more than 15 Hounsfield units (HU) on CT imaging are considered suggestive of renal cell carcinoma, whereas those with less than 10 HU of enhancement are more likely to be benign. Enhancement in the range of 10 to 15 HU is considered equivocal.
Differential diagnosis
By far, most small renal masses are renal cell carcinomas. However, other possibilities include oncocytoma, atypical or fat-poor angiomyolipoma, metanephric adenoma, urothelial carcinoma, metastatic lesions, lymphoma, renal abscess or infarction, mixed epithelial or stromal tumor, pseudotumor, and vascular malformations.
With rare exceptions, dense fat within a renal mass reliably indicates benign angiomyolipoma, and all renal tumors should be reviewed carefully for this feature. Beyond this, no clinical or radiologic feature ensures that a small renal mass is benign.
Imaging’s inability to accurately classify these enhancing renal lesions has led to a renewed interest in renal mass sampling to aid in the evaluation of small renal masses.
RENAL MASS SAMPLING: SAFER, MORE ACCURATE THAN THOUGHT
Renal mass sampling (ie, biopsy) has traditionally had a restricted role in the management of small renal masses, limited specifically to patients with a clinical history suggesting renal lymphoma, carcinoma that had metastasized to the kidney, or primary renal abscess. However, this may be changing, with more interest in it as a way to subtype and stratify select patients with small renal masses, especially potential candidates for active surveillance.
Our thinking about renal mass sampling has changed substantially over the last 2 decades. Previously, it was not routinely performed, because of concern over high false-negative rates (commonly quoted as being as high as 18%) and its potential associated morbidity. A common perception was that a negative biopsy could not be trusted and, therefore, renal mass sampling would not ultimately change patient management. However, many of these false-negative results were actually “noninformative,” ie, cases in which the renal tumor could not be adequately sampled or the pathologist lacked a sufficient specimen to allow for a definitive diagnosis.
Recent evidence suggests that these concerns were exaggerated and that renal mass sampling is more accurate and safer than previously thought. A meta-analysis of studies done before 2001 found that the diagnostic accuracy of renal mass sampling averaged 82%, whereas contemporary series indicate that its accuracy in differentiating benign from malignant tumors is actually greater than 95%.12 In addition, false-negative rates are now consistently less than 1%.13
Furthermore, serious complications requiring clinical intervention or hospitalization occur in fewer than 1% of cases. Seeding of the needle tract with tumor cells, which was another concern, is also exceedingly rare for these small, well-circumscribed renal masses.12
Overall morbidity is low with renal mass sampling, which is routinely performed as an outpatient procedure using CT or ultrasono-graphic guidance and local anesthesia.
However, 10% of biopsy results are still noninformative. In this situation, biopsy can be repeated, or the mass can be surgically excised, or the patient can undergo conservative management if he or she is unfit or unwilling to undergo surgery.
The encouraging results with renal mass sampling have led to greater use of it at many centers in the evaluation and risk-stratification of patients with small renal masses. It may be especially useful in patients considering several treatment options.
For example, a 75-year-old patient with modest comorbidities and a 2.0-cm enhancing renal mass could be a candidate for partial nephrectomy, thermal ablation, or active surveillance, and a reasonable argument could be made for each of these options. Renal mass sampling in this instance could be instrumental in guiding this decision, as a tissue diagnosis of high-grade renal cell carcinoma would favor partial nephrectomy, whereas a diagnosis of “oncocytoma neoplasm” would support a more conservative approach.
Older, frail patients with significant comorbidities who are unlikely to be candidates for aggressive surgical management would not need renal mass sampling, as they will ultimately be managed with active surveillance or thermal ablation.
Recent studies have also indicated that molecular profiling through gene expression analysis or proteomic analysis can further improve the accuracy of renal mass sampling.14 This will likely be the holy grail for this field, allowing for truly rational management (Figure 2).
TREATMENT OPTIONS
Radical nephrectomy: Still the most common treatment
In the past, complete removal of the kidney was standard for nearly all renal masses suspected of being renal cell carcinomas. Partial nephrectomy was generally reserved for patients who had a solitary kidney, bilateral tumors, or preexisting chronic kidney disease.
Although the two procedures provide equivalent oncologic outcomes for clinical T1 lesions, Miller et al15 reported that, before 2001, only 20% of small renal masses in the United States were managed with partial nephrectomy. That percentage has increased modestly, but radical nephrectomy still predominates.
One explanation for why the radical procedure is done more frequently is that partial nephrectomy is more technically difficult, as it involves renal reconstruction. Furthermore, radical nephrectomy can almost always be performed via a minimally invasive approach, which is inherently appealing to patients and surgeons alike. Laparoscopic radical nephrectomy has been called “the great seductress” because of these considerations.16 However, total removal of the kidney comes at a great price—loss of renal function.
Over the last decade, various studies have highlighted the association between radical nephrectomy and the subsequent clinical onset of chronic kidney disease, and the potential correlations between chronic kidney disease and cardiovascular events and elevated mortality rates.17
In a landmark study, Huang et al18 evaluated the outcomes of 662 patients who had small renal masses, a “normal” serum creatinine concentration (≤ 124 μmol/L [1.4 mg/dL]), and a normal-appearing contralateral kidney who underwent radical or partial nephrectomy. Of these, 26% were found to have preexisting stage 3 chronic kidney disease (glomerular filtration rate < 60 mL/min/1.73 m2 as calculated using the Modification of Diet in Renal Disease equation). Additionally, 65% of patients treated with radical nephrectomy were found to have stage 3 chronic kidney disease after surgery vs 20% of patients managed with partial nephrectomy.
The misconception remains that the risk of chronic kidney disease after radical nephrectomy is insignificant, since the risk is low in renal transplant donors.19 However, renal transplant donors undergo stringent screening to ensure that their general health is good and that their renal function is robust, both of which are not true in many patients with small renal masses, particularly if they are elderly.
The overuse of radical nephrectomy is worrisome in light of the potential implications of chronic kidney disease, such as increased risk of morbid cardiovascular events and elevated mortality rates. Many experts believe that over-treatment of small renal masses may have contributed to the paradoxical increase in overall mortality rates observed with radical nephrectomy in some studies.4
Although radical nephrectomy remains an important treatment for locally advanced renal cell carcinoma, it should be performed for small renal masses only if nephron-sparing surgery is not feasible (Table 2).
Partial nephrectomy: The new gold standard for most patients
Over the last 5 years, greater emphasis has been placed on lessening the risk of chronic kidney disease in the management of all urologic conditions, including small renal masses.
The overuse of radical nephrectomy prompted the American Urological Association to commission a panel to provide guidelines for the management of clinical stage T1 renal masses.17 After an extensive review and rigorous meta-analysis, the panel concluded that partial nephrectomy is the gold standard for most patients (Table 1, Table 2).
Partial nephrectomy involves excision of the tumor with a small margin of normal tissue, preserving as much functional renal parenchyma as possible, followed by closure of the collecting system, suture ligation of any transected vessels, and reapproximation of the capsule. Tumor excision is usually performed during temporary occlusion of the renal vasculature, allowing for a bloodless field. Regional hypothermia (cold ischemia) can also be used to minimize ischemic injury.
Contemporary series have documented that partial and radical nephrectomy have comparable oncologic efficacy for patients with small renal masses.20,21 Local recurrence rates are only 1% to 2% with partial nephrectomy, and 5- and 10-year cancer-specific survival rates of 96% and 90% have been reported.22
Furthermore, some studies have shown that patients undergoing partial nephrectomy have higher overall survival rates than those managed with radical nephrectomy—perhaps in part due to greater preservation of renal function and a lower incidence of subsequent chronic kidney disease.23,24 At Cleveland Clinic, we are now studying the determinants of ultimate renal function after partial nephrectomy in an effort to minimize ischemic injury and optimize this technique.25
Complications. Partial nephrectomy does have a potential downside in that it carries a higher risk of urologic complications such as urine leak and postoperative hemorrhage, which is not surprising because it requires a reconstruction that must heal. In a recent meta-analysis, urologic complications occurred in 6.3% patients who underwent open partial nephrectomy and in 9.0% of patients who underwent laparoscopic partial nephrectomy.17 Fortunately, most complications associated with partial nephrectomy can be managed with conservative measures.
Postoperative bleeding occurs in about 1% to 2% of patients and is the most serious complication. However, it is typically managed with superselective embolization, which has a high success rate and facilitates renal preservation.
Urine leak occurs in about 3% to 5% of cases and almost always resolves with prolonged drainage, occasionally complemented with a ureteral stent to promote antegrade drainage.
A new refinement, robotic-assisted partial nephrectomy promises to reduce the morbidity of this procedure. This approach takes less time to learn than standard laparoscopic surgery and has expanded the indications for minimally invasive partial nephrectomy, although more-difficult cases are still better done through a traditional, open surgical approach.
Thermal ablation: Another minimally invasive option
Cryoablation and radiofrequency ablation (collectively called thermal ablation) have recently emerged as alternate minimally invasive treatments for small renal masses. They are appealing options for patients with small renal tumors (< 3.5 cm) who have significant comorbidities but still prefer a proactive approach. They can also be considered as salvage procedures in patients with local recurrence after partial nephrectomy or in select patients with multifocal disease.
Both procedures can be performed percutaneously or laparoscopically, offering the potential for rapid convalescence and reduced morbidity.26,27 A laparoscopic approach is necessary to mobilize the tumor from adjacent organs if they are juxtaposed, whereas a percutaneous approach is less invasive and is better suited for posterior renal masses.28 Renal mass sampling should be performed in these patients before treatment to define the histology and to guide surveillance and should be repeated postoperatively if there is suspicion of local recurrence based on imaging.
Cryoablation destroys tumor cells through rapid cycles of freezing to less than −20°C (−4°F) and thawing, which can be monitored in real time via thermocoupling (ie, a thermometer microprobe strategically placed outside the tumor to ensure that lethal temperatures are extended beyond the edge of the tumor) or via ultrasonography, or both. Treatment is continued until the “ice ball” extends about 1 cm beyond the edge of the tumor.
Initial series reported local tumor control rates in the range of 90% to 95%; however, follow-up was very limited.29 In a more robust single-institution experience,30 renal cryoablation demonstrated 5-year cancer-specific and recurrence-free survival rates of 93% and 83%, respectively, substantially lower than what would be expected with surgical excision in a similar patient population.
Another concern with cryoablation is that options are limited for surgical salvage if the initial treatment fails. Nguyen and Campbell31 reported that partial nephrectomy and minimally invasive surgery were often precluded in this situation because of the extensive fibrotic reaction caused by the prior treatment. If cryoablation fails, surgical salvage thus often requires open, radical surgery.
Radiofrequency ablation produces tumor coagulation via protein denaturation and disruption of cell membranes after heating tissues to temperatures above 50°C (122°F) for 4 to 6 minutes.32 One of its disadvantages is that one cannot monitor treatment progress in real time, as there is no identifiable change in tissue appearance analagous to the ice ball that is seen with cryoablation.
Although the outcomes of radiofrequency ablation are less robust than those of cryoablation, most studies suggest that local control is achieved in 80% to 90% of cases based on radiographic loss of enhancement after treatment.17,30,33 A recent meta-analysis comparing these treatments found that lesions treated with radiofrequency ablation had a significantly higher rate of local tumor progression than those treated with cryoablation (12.3% vs 4.7%, P < .0001).34 Both of these local recurrence rates are substantially higher than that seen after surgical excision, despite much shorter follow-up after thermal ablation.
Tempered enthusiasm. Because thermal ablation has been developed relatively recently, its long-term outcomes and treatment efficacy have not been well established, and current studies have confirmed higher local recurrence rates with thermal ablation than with surgical excision (Table 1). Furthermore, there are significant deficiencies in the literature about thermal ablation, including limited follow-up, lack of pathologic confirmation, and controversies regarding histologic or radiologic definitions of success (Table 2).
Although current enthusiasm for thermal ablation has been tempered by suboptimal results, further refinement in technique and acknowledgment of its limitations will help to define appropriate candidates for these treatments.
Active surveillance for select patients
In select patients with extensive medical comorbidities or short life expectancy, the risks associated with proactive management may outweigh the benefits, especially considering the indolent nature of many small renal masses. In such patients, active surveillance is reasonable.
A recent meta-analysis found that most small enhancing renal masses grew relatively slowly (median 0.28 cm/year) and posed a low risk of metastasis (1%–2%).17,22 Furthermore, almost all renal lesions that progressed to metastatic disease demonstrated rapid radiographic growth, suggesting that the radiographic growth of a renal mass under active surveillance may serve as an indicator for aggressive behavior.35
Unfortunately, the growth rates of small renal masses do not reliably predict malignancy, and one study reported that 83% of tumors without demonstrable growth were malignant.36
Studies of active surveillance to date have had several other important limitations. Many did not incorporate pathologic confirmation, so that about 20% of the tumors were actually benign, thus artificially reducing the risk of adverse outcomes.5,22,37 Furthermore, the follow-up has been short, with most studies including data for only 2 to 3 years, which is clearly inadequate for this type of malignancy.37,38 Finally, most series had significant selection bias towards small, homogenous masses. In general, small renal masses that appear to be more aggressive are treated and thus excluded from these surveillance populations (Table 2).
Another concern about active surveillance is the small but real risk of tumor progression to metastatic disease, rendering these patients incurable even with new, targeted molecular therapies. Additionally, some patients may lose their window of opportunity for nephron-sparing surgery if significant tumor growth occurs during observation, rendering partial nephrectomy unfeasible. Therefore, active surveillance is not advisable for young, otherwise healthy patients (Table 2).
In the future, advances in renal mass sampling with molecular profiling may help determine which renal lesions are less biologically aggressive and, thereby, help identify appropriate candidates for observation (Figure 2).
- Chow WH, Devesa SS. Contemporary epidemiology of renal cell cancer. Cancer J 2008; 14:288–301.
- Lane BR, Campbell SC. Management of small renal masses. AUA Update Series 2009; 28:313–324.
- Volpe A, Panzarella T, Rendon RA, Haider MA, Kondylis FI, Jewett MA. The natural history of incidentally detected small renal masses. Cancer 2004; 100:738–745.
- Hollingsworth JM, Miller DC, Daignault S, Hollenbeck BK. Rising incidence of small renal masses: a need to reassess treatment effect. J Natl Cancer Inst 2006; 98:1331–1334.
- Frank I, Blute ML, Cheville JC, Lohse CM, Weaver AL, Zincke H. Solid renal tumors: an analysis of pathological features related to tumor size. J Urol 2003; 170:2217–2220.
- Russo P. Should elective partial nephrectomy be performed for renal cell carcinoma >4 cm in size? Nat Clin Pract Urol 2008; 5:482–483.
- Thomas AA, Aron M, Hernandez AV, Lane BR, Gill IS. Laparoscopic partial nephrectomy in octogenarians. Urology 2009; 74:1042–1046.
- Thompson RH, Kurta JM, Kaag M, et al. Tumor size is associated with malignant potential in renal cell carcinoma cases. J Urol 2009; 181:2033–2036.
- Mues AC, Landman J. Small renal masses: current concepts regarding the natural history and reflections on the American Urological Association guidelines. Curr Opin Urol 2010; 20:105–110.
- Patard JJ, Bensalah K, Vincendeau S, Rioux-Leclerq N, Guillé F, Lobel B. [Correlation between the mode of presentation of renal tumors and patient survival]. Prog Urol 2003; 13:23–28.
- Rini BI, Campbell SC, Escudier B. Renal cell carcinoma. Lancet 2009; 373:1119–1132.
- Lane BR, Samplaski MK, Herts BR, Zhou M, Novick AC, Campbell SC. Renal mass biopsy—a renaissance? J Urol 2008; 179:20–27.
- Samplaski MK, Zhou M, Lane BR, Herts B, Campbell SC. Renal mass sampling: an enlightened perspective. Int J Urol 2011; 18:5–19.
- Tan MH, Rogers CG, Cooper JT, et al. Gene expression profiling of renal cell carcinoma. Clin Cancer Res 2004; 10:6315S–6321S.
- Miller DC, Hollingsworth JM, Hafez KS, Daignault S, Hollenbeck BK. Partial nephrectomy for small renal masses: an emerging quality of care concern? J Urol 2006; 175:853–857.
- Lane BR, Poggio ED, Herts BR, Novick AC, Campbell SC. Renal function assessment in the era of chronic kidney disease: renewed emphasis on renal function centered patient care. J Urol 2009; 182:435–444.
- Campbell SC, Novick AC, Belldegrun A, et al; Practice Guidelines Committee of the American Urological Association. Guideline for management of the clinical T1 renal mass. J Urol 2009; 182:1271–1279.
- Huang WC, Levey AS, Serio AM, et al. Chronic kidney disease after nephrectomy in patients with renal cortical tumours: a retrospective cohort study. Lancet Oncol 2006; 7:735–740.
- Boorjian SA, Uzzo RG. The evolving management of small renal masses. Curr Oncol Rep 2009; 11:211–217.
- Hafez KS, Fergany AF, Novick AC. Nephron sparing surgery for localized renal cell carcinoma: impact of tumor size on patient survival, tumor recurrence and TNM staging. J Urol 1999; 162:1930–1933.
- Lee CT, Katz J, Shi W, Thaler HT, Reuter VE, Russo P. Surgical management of renal tumors 4 cm. or less in a contemporary cohort. J Urol 2000; 163:730–736.
- Chawla SN, Crispen PL, Hanlon AL, Greenberg RE, Chen DY, Uzzo RG. The natural history of observed enhancing renal masses: meta-analysis and review of the world literature. J Urol 2006; 175:425–431.
- Huang WC, Elkin EB, Levey AS, Jang TL, Russo P. Partial nephrectomy versus radical nephrectomy in patients with small renal tumors—is there a difference in mortality and cardiovascular outcomes? J Urol 2009; 181:55–61.
- Thompson RH, Boorjian SA, Lohse CM, et al. Radical nephrectomy for pT1a renal masses may be associated with decreased overall survival compared with partial nephrectomy. J Urol 2008; 179:468–471.
- Thomas AA, Demirjian S, Lane BR, et al. Acute kidney injury: novel biomarkers and potential utility for patient care in urology. Urology 2011; 77:5–11.
- Hinshaw JL, Shadid AM, Nakada SY, Hedican SP, Winter TC, Lee FT. Comparison of percutaneous and laparoscopic cryoablation for the treatment of solid renal masses. AJR Am J Roentgenol 2008; 191:1159–1168.
- Sterrett SP, Nakada SY, Wingo MS, Williams SK, Leveillee RJ. Renal thermal ablative therapy. Urol Clin North Am 2008; 35:397–414.
- Hafron J, Kaouk JH. Ablative techniques for the management of kidney cancer. Nat Clin Pract Urol 2007; 4:261–269.
- Matin SF, Ahrar K. Nephron-sparing probe ablative therapy: longterm outcomes. Curr Opin Urol 2008; 18:150–156.
- Berger A, Kamoi K, Gill IS, Aron M. Cryoablation for renal tumors: current status. Curr Opin Urol 2009; 19:138–142.
- Nguyen CT, Campbell SC. Salvage of local recurrence after primary thermal ablation for small renal masses. Expert Rev Anticancer Ther 2008; 8:1899–1905.
- Goldberg SN, Gazelle GS, Mueller PR. Thermal ablation therapy for focal malignancy: a unified approach to underlying principles, techniques, and diagnostic imaging guidance. AJR Am J Roentgenol 2000; 174:323–331.
- Carraway WA, Raman JD, Cadeddu JA. Current status of renal radiofrequency ablation. Curr Opin Urol 2009; 19:143–147.
- Kunkle DA, Uzzo RG. Cryoablation or radiofrequency ablation of the small renal mass: a meta-analysis. Cancer 2008; 113:2671–2680.
- Kunkle DA, Kutikov A, Uzzo RG. Management of small renal masses. Semin Ultrasound CT MR 2009; 30:352–358.
- Kunkle DA, Crispen PL, Chen DY, Greenberg RE, Uzzo RG. Enhancing renal masses with zero net growth during active surveillance. J Urol 2007; 177:849–853.
- Kunkle DA, Egleston BL, Uzzo RG. Excise, ablate or observe: the small renal mass dilemma—a meta-analysis and review. J Urol 2008; 179:1227–1233.
- Jewett MA, Zuniga A. Renal tumor natural history: the rationale and role for active surveillance. Urol Clin North Am 2008; 35:627–634.
Opinion about treatment of mall renal masses has changed considerably in the past 2 decades.
Traditionally, the most common treatment was surgical removal of the whole kidney, ie, radical nephrectomy. However, recent studies have shown that many patients who undergo radical nephrectomy develop chronic kidney disease. Furthermore, radical nephrectomy often constitutes over-treatment, as many of these lesions are benign or, if malignant, would follow an indolent course if left alone.
Now that we better understand the biology of small renal masses and are more aware of the morbidity and mortality related to chronic kidney disease, we try to avoid radical nephrectomy whenever possible, favoring nephron-sparing approaches instead.
In this article, we review the current clinical management of small renal masses.
SMALL RENAL MASSES ARE A HETEROGENEOUS GROUP
Small renal masses are defined as solid renal tumors that enhance on computed tomography (CT) and magnetic resonance imaging (MRI) and are suspected of being renal cell carcinomas. They are generally low-stage and relatively small (< 4 cm in diameter) at presentation. Most are now discovered incidentally on CT or MRI done for various abdominal symptoms. From 20,000 to 30,000 new cases are diagnosed each year in the United States, and the rate is increasing by 3% to 4% per year as the use of CT and MRI increases.1,2
With more small renal masses being detected incidentally, renal cell carcinoma has been going through a stage and size migration—ie, more of these tumors are being discovered in clinical stage T1 (ie, confined to the kidney and measuring less than 7 cm) than in the past. Currently, clinical T1 renal tumors account for 48% to 66% of cases.3
This indicates that the disease is being detected and treated earlier in its course than in the past. However, cancer-specific deaths from renal cell carcinoma have not declined, suggesting that for many of these patients, our traditional practice of aggressive surgical management with radical nephrectomy may not be warranted.4
Small renal masses vary in biologic aggressiveness
Recent large surgical series indicate that up to 20% of small renal masses are benign, 55% to 60% are indolent renal cell carcinomas, and only 20% to 25% have potentially aggressive features, defined by high nuclear grade or locally invasive characteristics.5–7
A relatively strong predictor of the aggressiveness of renal tumors is their size, which directly correlates with the risk of malignant pathology. Of lesions smaller than 1.0 cm, 38% to 46% are benign, dramatically decreasing to 6.3% to 7.1% for lesions larger than 7.0 cm.5 Each 1.0-cm increase in tumor diameter correlates with a 16% increase in the risk of malignancy.8
Our knowledge of the natural history of small renal masses is limited, being based on small, retrospective series. In these studies, when small renal masses were followed over time, relatively few progressed (ie, metastasized), and there have been no documented reports of disease progression in the absence of demonstrable tumor growth, suggesting a predominance of nonaggressive phenotypes.9
In light of these observations, patients with small renal masses should be carefully evaluated to determine if they are candidates for active surveillance as opposed to more aggressive treatment, ie, surgery or thermal ablation.
CT AND MRI ARE THE PREFERRED DIAGNOSTIC STUDIES
In the past, most patients with renal tumors presented with gross hematuria, flank pain, or a palpable abdominal mass. These presentations are now uncommon, as most cases are asymptomatic and are diagnosed incidentally. In a series of 349 small renal masses, microhematuria was found in only 8 cases.10
Systemic manifestations or paraneoplastic syndromes such as hypercalcemia or hypertension are more common in patients with metastatic renal cell carcinoma than in those with localized tumors. It was because of these varied clinical presentations that renal cell carcinoma was previously known as the “internist’s tumor”; however, small renal masses are better termed the “radiologist’s tumor.”11
High-quality axial imaging with CT or MRI is preferred for evaluating renal cortical neoplasms. Enhancement on CT or MRI is the characteristic finding of a renal lesion that should be suspected of being renal cell carcinoma (Figure 1). Triple-phase CT is ideal, with images taken before contrast is given, immediately after contrast (the early vascular phase), and later (the delayed phase). Alternatively, MRI can be used in patients who are allergic to intravenous contrast or who have moderate renal dysfunction.
Renal tumors with enhancement of more than 15 Hounsfield units (HU) on CT imaging are considered suggestive of renal cell carcinoma, whereas those with less than 10 HU of enhancement are more likely to be benign. Enhancement in the range of 10 to 15 HU is considered equivocal.
Differential diagnosis
By far, most small renal masses are renal cell carcinomas. However, other possibilities include oncocytoma, atypical or fat-poor angiomyolipoma, metanephric adenoma, urothelial carcinoma, metastatic lesions, lymphoma, renal abscess or infarction, mixed epithelial or stromal tumor, pseudotumor, and vascular malformations.
With rare exceptions, dense fat within a renal mass reliably indicates benign angiomyolipoma, and all renal tumors should be reviewed carefully for this feature. Beyond this, no clinical or radiologic feature ensures that a small renal mass is benign.
Imaging’s inability to accurately classify these enhancing renal lesions has led to a renewed interest in renal mass sampling to aid in the evaluation of small renal masses.
RENAL MASS SAMPLING: SAFER, MORE ACCURATE THAN THOUGHT
Renal mass sampling (ie, biopsy) has traditionally had a restricted role in the management of small renal masses, limited specifically to patients with a clinical history suggesting renal lymphoma, carcinoma that had metastasized to the kidney, or primary renal abscess. However, this may be changing, with more interest in it as a way to subtype and stratify select patients with small renal masses, especially potential candidates for active surveillance.
Our thinking about renal mass sampling has changed substantially over the last 2 decades. Previously, it was not routinely performed, because of concern over high false-negative rates (commonly quoted as being as high as 18%) and its potential associated morbidity. A common perception was that a negative biopsy could not be trusted and, therefore, renal mass sampling would not ultimately change patient management. However, many of these false-negative results were actually “noninformative,” ie, cases in which the renal tumor could not be adequately sampled or the pathologist lacked a sufficient specimen to allow for a definitive diagnosis.
Recent evidence suggests that these concerns were exaggerated and that renal mass sampling is more accurate and safer than previously thought. A meta-analysis of studies done before 2001 found that the diagnostic accuracy of renal mass sampling averaged 82%, whereas contemporary series indicate that its accuracy in differentiating benign from malignant tumors is actually greater than 95%.12 In addition, false-negative rates are now consistently less than 1%.13
Furthermore, serious complications requiring clinical intervention or hospitalization occur in fewer than 1% of cases. Seeding of the needle tract with tumor cells, which was another concern, is also exceedingly rare for these small, well-circumscribed renal masses.12
Overall morbidity is low with renal mass sampling, which is routinely performed as an outpatient procedure using CT or ultrasono-graphic guidance and local anesthesia.
However, 10% of biopsy results are still noninformative. In this situation, biopsy can be repeated, or the mass can be surgically excised, or the patient can undergo conservative management if he or she is unfit or unwilling to undergo surgery.
The encouraging results with renal mass sampling have led to greater use of it at many centers in the evaluation and risk-stratification of patients with small renal masses. It may be especially useful in patients considering several treatment options.
For example, a 75-year-old patient with modest comorbidities and a 2.0-cm enhancing renal mass could be a candidate for partial nephrectomy, thermal ablation, or active surveillance, and a reasonable argument could be made for each of these options. Renal mass sampling in this instance could be instrumental in guiding this decision, as a tissue diagnosis of high-grade renal cell carcinoma would favor partial nephrectomy, whereas a diagnosis of “oncocytoma neoplasm” would support a more conservative approach.
Older, frail patients with significant comorbidities who are unlikely to be candidates for aggressive surgical management would not need renal mass sampling, as they will ultimately be managed with active surveillance or thermal ablation.
Recent studies have also indicated that molecular profiling through gene expression analysis or proteomic analysis can further improve the accuracy of renal mass sampling.14 This will likely be the holy grail for this field, allowing for truly rational management (Figure 2).
TREATMENT OPTIONS
Radical nephrectomy: Still the most common treatment
In the past, complete removal of the kidney was standard for nearly all renal masses suspected of being renal cell carcinomas. Partial nephrectomy was generally reserved for patients who had a solitary kidney, bilateral tumors, or preexisting chronic kidney disease.
Although the two procedures provide equivalent oncologic outcomes for clinical T1 lesions, Miller et al15 reported that, before 2001, only 20% of small renal masses in the United States were managed with partial nephrectomy. That percentage has increased modestly, but radical nephrectomy still predominates.
One explanation for why the radical procedure is done more frequently is that partial nephrectomy is more technically difficult, as it involves renal reconstruction. Furthermore, radical nephrectomy can almost always be performed via a minimally invasive approach, which is inherently appealing to patients and surgeons alike. Laparoscopic radical nephrectomy has been called “the great seductress” because of these considerations.16 However, total removal of the kidney comes at a great price—loss of renal function.
Over the last decade, various studies have highlighted the association between radical nephrectomy and the subsequent clinical onset of chronic kidney disease, and the potential correlations between chronic kidney disease and cardiovascular events and elevated mortality rates.17
In a landmark study, Huang et al18 evaluated the outcomes of 662 patients who had small renal masses, a “normal” serum creatinine concentration (≤ 124 μmol/L [1.4 mg/dL]), and a normal-appearing contralateral kidney who underwent radical or partial nephrectomy. Of these, 26% were found to have preexisting stage 3 chronic kidney disease (glomerular filtration rate < 60 mL/min/1.73 m2 as calculated using the Modification of Diet in Renal Disease equation). Additionally, 65% of patients treated with radical nephrectomy were found to have stage 3 chronic kidney disease after surgery vs 20% of patients managed with partial nephrectomy.
The misconception remains that the risk of chronic kidney disease after radical nephrectomy is insignificant, since the risk is low in renal transplant donors.19 However, renal transplant donors undergo stringent screening to ensure that their general health is good and that their renal function is robust, both of which are not true in many patients with small renal masses, particularly if they are elderly.
The overuse of radical nephrectomy is worrisome in light of the potential implications of chronic kidney disease, such as increased risk of morbid cardiovascular events and elevated mortality rates. Many experts believe that over-treatment of small renal masses may have contributed to the paradoxical increase in overall mortality rates observed with radical nephrectomy in some studies.4
Although radical nephrectomy remains an important treatment for locally advanced renal cell carcinoma, it should be performed for small renal masses only if nephron-sparing surgery is not feasible (Table 2).
Partial nephrectomy: The new gold standard for most patients
Over the last 5 years, greater emphasis has been placed on lessening the risk of chronic kidney disease in the management of all urologic conditions, including small renal masses.
The overuse of radical nephrectomy prompted the American Urological Association to commission a panel to provide guidelines for the management of clinical stage T1 renal masses.17 After an extensive review and rigorous meta-analysis, the panel concluded that partial nephrectomy is the gold standard for most patients (Table 1, Table 2).
Partial nephrectomy involves excision of the tumor with a small margin of normal tissue, preserving as much functional renal parenchyma as possible, followed by closure of the collecting system, suture ligation of any transected vessels, and reapproximation of the capsule. Tumor excision is usually performed during temporary occlusion of the renal vasculature, allowing for a bloodless field. Regional hypothermia (cold ischemia) can also be used to minimize ischemic injury.
Contemporary series have documented that partial and radical nephrectomy have comparable oncologic efficacy for patients with small renal masses.20,21 Local recurrence rates are only 1% to 2% with partial nephrectomy, and 5- and 10-year cancer-specific survival rates of 96% and 90% have been reported.22
Furthermore, some studies have shown that patients undergoing partial nephrectomy have higher overall survival rates than those managed with radical nephrectomy—perhaps in part due to greater preservation of renal function and a lower incidence of subsequent chronic kidney disease.23,24 At Cleveland Clinic, we are now studying the determinants of ultimate renal function after partial nephrectomy in an effort to minimize ischemic injury and optimize this technique.25
Complications. Partial nephrectomy does have a potential downside in that it carries a higher risk of urologic complications such as urine leak and postoperative hemorrhage, which is not surprising because it requires a reconstruction that must heal. In a recent meta-analysis, urologic complications occurred in 6.3% patients who underwent open partial nephrectomy and in 9.0% of patients who underwent laparoscopic partial nephrectomy.17 Fortunately, most complications associated with partial nephrectomy can be managed with conservative measures.
Postoperative bleeding occurs in about 1% to 2% of patients and is the most serious complication. However, it is typically managed with superselective embolization, which has a high success rate and facilitates renal preservation.
Urine leak occurs in about 3% to 5% of cases and almost always resolves with prolonged drainage, occasionally complemented with a ureteral stent to promote antegrade drainage.
A new refinement, robotic-assisted partial nephrectomy promises to reduce the morbidity of this procedure. This approach takes less time to learn than standard laparoscopic surgery and has expanded the indications for minimally invasive partial nephrectomy, although more-difficult cases are still better done through a traditional, open surgical approach.
Thermal ablation: Another minimally invasive option
Cryoablation and radiofrequency ablation (collectively called thermal ablation) have recently emerged as alternate minimally invasive treatments for small renal masses. They are appealing options for patients with small renal tumors (< 3.5 cm) who have significant comorbidities but still prefer a proactive approach. They can also be considered as salvage procedures in patients with local recurrence after partial nephrectomy or in select patients with multifocal disease.
Both procedures can be performed percutaneously or laparoscopically, offering the potential for rapid convalescence and reduced morbidity.26,27 A laparoscopic approach is necessary to mobilize the tumor from adjacent organs if they are juxtaposed, whereas a percutaneous approach is less invasive and is better suited for posterior renal masses.28 Renal mass sampling should be performed in these patients before treatment to define the histology and to guide surveillance and should be repeated postoperatively if there is suspicion of local recurrence based on imaging.
Cryoablation destroys tumor cells through rapid cycles of freezing to less than −20°C (−4°F) and thawing, which can be monitored in real time via thermocoupling (ie, a thermometer microprobe strategically placed outside the tumor to ensure that lethal temperatures are extended beyond the edge of the tumor) or via ultrasonography, or both. Treatment is continued until the “ice ball” extends about 1 cm beyond the edge of the tumor.
Initial series reported local tumor control rates in the range of 90% to 95%; however, follow-up was very limited.29 In a more robust single-institution experience,30 renal cryoablation demonstrated 5-year cancer-specific and recurrence-free survival rates of 93% and 83%, respectively, substantially lower than what would be expected with surgical excision in a similar patient population.
Another concern with cryoablation is that options are limited for surgical salvage if the initial treatment fails. Nguyen and Campbell31 reported that partial nephrectomy and minimally invasive surgery were often precluded in this situation because of the extensive fibrotic reaction caused by the prior treatment. If cryoablation fails, surgical salvage thus often requires open, radical surgery.
Radiofrequency ablation produces tumor coagulation via protein denaturation and disruption of cell membranes after heating tissues to temperatures above 50°C (122°F) for 4 to 6 minutes.32 One of its disadvantages is that one cannot monitor treatment progress in real time, as there is no identifiable change in tissue appearance analagous to the ice ball that is seen with cryoablation.
Although the outcomes of radiofrequency ablation are less robust than those of cryoablation, most studies suggest that local control is achieved in 80% to 90% of cases based on radiographic loss of enhancement after treatment.17,30,33 A recent meta-analysis comparing these treatments found that lesions treated with radiofrequency ablation had a significantly higher rate of local tumor progression than those treated with cryoablation (12.3% vs 4.7%, P < .0001).34 Both of these local recurrence rates are substantially higher than that seen after surgical excision, despite much shorter follow-up after thermal ablation.
Tempered enthusiasm. Because thermal ablation has been developed relatively recently, its long-term outcomes and treatment efficacy have not been well established, and current studies have confirmed higher local recurrence rates with thermal ablation than with surgical excision (Table 1). Furthermore, there are significant deficiencies in the literature about thermal ablation, including limited follow-up, lack of pathologic confirmation, and controversies regarding histologic or radiologic definitions of success (Table 2).
Although current enthusiasm for thermal ablation has been tempered by suboptimal results, further refinement in technique and acknowledgment of its limitations will help to define appropriate candidates for these treatments.
Active surveillance for select patients
In select patients with extensive medical comorbidities or short life expectancy, the risks associated with proactive management may outweigh the benefits, especially considering the indolent nature of many small renal masses. In such patients, active surveillance is reasonable.
A recent meta-analysis found that most small enhancing renal masses grew relatively slowly (median 0.28 cm/year) and posed a low risk of metastasis (1%–2%).17,22 Furthermore, almost all renal lesions that progressed to metastatic disease demonstrated rapid radiographic growth, suggesting that the radiographic growth of a renal mass under active surveillance may serve as an indicator for aggressive behavior.35
Unfortunately, the growth rates of small renal masses do not reliably predict malignancy, and one study reported that 83% of tumors without demonstrable growth were malignant.36
Studies of active surveillance to date have had several other important limitations. Many did not incorporate pathologic confirmation, so that about 20% of the tumors were actually benign, thus artificially reducing the risk of adverse outcomes.5,22,37 Furthermore, the follow-up has been short, with most studies including data for only 2 to 3 years, which is clearly inadequate for this type of malignancy.37,38 Finally, most series had significant selection bias towards small, homogenous masses. In general, small renal masses that appear to be more aggressive are treated and thus excluded from these surveillance populations (Table 2).
Another concern about active surveillance is the small but real risk of tumor progression to metastatic disease, rendering these patients incurable even with new, targeted molecular therapies. Additionally, some patients may lose their window of opportunity for nephron-sparing surgery if significant tumor growth occurs during observation, rendering partial nephrectomy unfeasible. Therefore, active surveillance is not advisable for young, otherwise healthy patients (Table 2).
In the future, advances in renal mass sampling with molecular profiling may help determine which renal lesions are less biologically aggressive and, thereby, help identify appropriate candidates for observation (Figure 2).
Opinion about treatment of mall renal masses has changed considerably in the past 2 decades.
Traditionally, the most common treatment was surgical removal of the whole kidney, ie, radical nephrectomy. However, recent studies have shown that many patients who undergo radical nephrectomy develop chronic kidney disease. Furthermore, radical nephrectomy often constitutes over-treatment, as many of these lesions are benign or, if malignant, would follow an indolent course if left alone.
Now that we better understand the biology of small renal masses and are more aware of the morbidity and mortality related to chronic kidney disease, we try to avoid radical nephrectomy whenever possible, favoring nephron-sparing approaches instead.
In this article, we review the current clinical management of small renal masses.
SMALL RENAL MASSES ARE A HETEROGENEOUS GROUP
Small renal masses are defined as solid renal tumors that enhance on computed tomography (CT) and magnetic resonance imaging (MRI) and are suspected of being renal cell carcinomas. They are generally low-stage and relatively small (< 4 cm in diameter) at presentation. Most are now discovered incidentally on CT or MRI done for various abdominal symptoms. From 20,000 to 30,000 new cases are diagnosed each year in the United States, and the rate is increasing by 3% to 4% per year as the use of CT and MRI increases.1,2
With more small renal masses being detected incidentally, renal cell carcinoma has been going through a stage and size migration—ie, more of these tumors are being discovered in clinical stage T1 (ie, confined to the kidney and measuring less than 7 cm) than in the past. Currently, clinical T1 renal tumors account for 48% to 66% of cases.3
This indicates that the disease is being detected and treated earlier in its course than in the past. However, cancer-specific deaths from renal cell carcinoma have not declined, suggesting that for many of these patients, our traditional practice of aggressive surgical management with radical nephrectomy may not be warranted.4
Small renal masses vary in biologic aggressiveness
Recent large surgical series indicate that up to 20% of small renal masses are benign, 55% to 60% are indolent renal cell carcinomas, and only 20% to 25% have potentially aggressive features, defined by high nuclear grade or locally invasive characteristics.5–7
A relatively strong predictor of the aggressiveness of renal tumors is their size, which directly correlates with the risk of malignant pathology. Of lesions smaller than 1.0 cm, 38% to 46% are benign, dramatically decreasing to 6.3% to 7.1% for lesions larger than 7.0 cm.5 Each 1.0-cm increase in tumor diameter correlates with a 16% increase in the risk of malignancy.8
Our knowledge of the natural history of small renal masses is limited, being based on small, retrospective series. In these studies, when small renal masses were followed over time, relatively few progressed (ie, metastasized), and there have been no documented reports of disease progression in the absence of demonstrable tumor growth, suggesting a predominance of nonaggressive phenotypes.9
In light of these observations, patients with small renal masses should be carefully evaluated to determine if they are candidates for active surveillance as opposed to more aggressive treatment, ie, surgery or thermal ablation.
CT AND MRI ARE THE PREFERRED DIAGNOSTIC STUDIES
In the past, most patients with renal tumors presented with gross hematuria, flank pain, or a palpable abdominal mass. These presentations are now uncommon, as most cases are asymptomatic and are diagnosed incidentally. In a series of 349 small renal masses, microhematuria was found in only 8 cases.10
Systemic manifestations or paraneoplastic syndromes such as hypercalcemia or hypertension are more common in patients with metastatic renal cell carcinoma than in those with localized tumors. It was because of these varied clinical presentations that renal cell carcinoma was previously known as the “internist’s tumor”; however, small renal masses are better termed the “radiologist’s tumor.”11
High-quality axial imaging with CT or MRI is preferred for evaluating renal cortical neoplasms. Enhancement on CT or MRI is the characteristic finding of a renal lesion that should be suspected of being renal cell carcinoma (Figure 1). Triple-phase CT is ideal, with images taken before contrast is given, immediately after contrast (the early vascular phase), and later (the delayed phase). Alternatively, MRI can be used in patients who are allergic to intravenous contrast or who have moderate renal dysfunction.
Renal tumors with enhancement of more than 15 Hounsfield units (HU) on CT imaging are considered suggestive of renal cell carcinoma, whereas those with less than 10 HU of enhancement are more likely to be benign. Enhancement in the range of 10 to 15 HU is considered equivocal.
Differential diagnosis
By far, most small renal masses are renal cell carcinomas. However, other possibilities include oncocytoma, atypical or fat-poor angiomyolipoma, metanephric adenoma, urothelial carcinoma, metastatic lesions, lymphoma, renal abscess or infarction, mixed epithelial or stromal tumor, pseudotumor, and vascular malformations.
With rare exceptions, dense fat within a renal mass reliably indicates benign angiomyolipoma, and all renal tumors should be reviewed carefully for this feature. Beyond this, no clinical or radiologic feature ensures that a small renal mass is benign.
Imaging’s inability to accurately classify these enhancing renal lesions has led to a renewed interest in renal mass sampling to aid in the evaluation of small renal masses.
RENAL MASS SAMPLING: SAFER, MORE ACCURATE THAN THOUGHT
Renal mass sampling (ie, biopsy) has traditionally had a restricted role in the management of small renal masses, limited specifically to patients with a clinical history suggesting renal lymphoma, carcinoma that had metastasized to the kidney, or primary renal abscess. However, this may be changing, with more interest in it as a way to subtype and stratify select patients with small renal masses, especially potential candidates for active surveillance.
Our thinking about renal mass sampling has changed substantially over the last 2 decades. Previously, it was not routinely performed, because of concern over high false-negative rates (commonly quoted as being as high as 18%) and its potential associated morbidity. A common perception was that a negative biopsy could not be trusted and, therefore, renal mass sampling would not ultimately change patient management. However, many of these false-negative results were actually “noninformative,” ie, cases in which the renal tumor could not be adequately sampled or the pathologist lacked a sufficient specimen to allow for a definitive diagnosis.
Recent evidence suggests that these concerns were exaggerated and that renal mass sampling is more accurate and safer than previously thought. A meta-analysis of studies done before 2001 found that the diagnostic accuracy of renal mass sampling averaged 82%, whereas contemporary series indicate that its accuracy in differentiating benign from malignant tumors is actually greater than 95%.12 In addition, false-negative rates are now consistently less than 1%.13
Furthermore, serious complications requiring clinical intervention or hospitalization occur in fewer than 1% of cases. Seeding of the needle tract with tumor cells, which was another concern, is also exceedingly rare for these small, well-circumscribed renal masses.12
Overall morbidity is low with renal mass sampling, which is routinely performed as an outpatient procedure using CT or ultrasono-graphic guidance and local anesthesia.
However, 10% of biopsy results are still noninformative. In this situation, biopsy can be repeated, or the mass can be surgically excised, or the patient can undergo conservative management if he or she is unfit or unwilling to undergo surgery.
The encouraging results with renal mass sampling have led to greater use of it at many centers in the evaluation and risk-stratification of patients with small renal masses. It may be especially useful in patients considering several treatment options.
For example, a 75-year-old patient with modest comorbidities and a 2.0-cm enhancing renal mass could be a candidate for partial nephrectomy, thermal ablation, or active surveillance, and a reasonable argument could be made for each of these options. Renal mass sampling in this instance could be instrumental in guiding this decision, as a tissue diagnosis of high-grade renal cell carcinoma would favor partial nephrectomy, whereas a diagnosis of “oncocytoma neoplasm” would support a more conservative approach.
Older, frail patients with significant comorbidities who are unlikely to be candidates for aggressive surgical management would not need renal mass sampling, as they will ultimately be managed with active surveillance or thermal ablation.
Recent studies have also indicated that molecular profiling through gene expression analysis or proteomic analysis can further improve the accuracy of renal mass sampling.14 This will likely be the holy grail for this field, allowing for truly rational management (Figure 2).
TREATMENT OPTIONS
Radical nephrectomy: Still the most common treatment
In the past, complete removal of the kidney was standard for nearly all renal masses suspected of being renal cell carcinomas. Partial nephrectomy was generally reserved for patients who had a solitary kidney, bilateral tumors, or preexisting chronic kidney disease.
Although the two procedures provide equivalent oncologic outcomes for clinical T1 lesions, Miller et al15 reported that, before 2001, only 20% of small renal masses in the United States were managed with partial nephrectomy. That percentage has increased modestly, but radical nephrectomy still predominates.
One explanation for why the radical procedure is done more frequently is that partial nephrectomy is more technically difficult, as it involves renal reconstruction. Furthermore, radical nephrectomy can almost always be performed via a minimally invasive approach, which is inherently appealing to patients and surgeons alike. Laparoscopic radical nephrectomy has been called “the great seductress” because of these considerations.16 However, total removal of the kidney comes at a great price—loss of renal function.
Over the last decade, various studies have highlighted the association between radical nephrectomy and the subsequent clinical onset of chronic kidney disease, and the potential correlations between chronic kidney disease and cardiovascular events and elevated mortality rates.17
In a landmark study, Huang et al18 evaluated the outcomes of 662 patients who had small renal masses, a “normal” serum creatinine concentration (≤ 124 μmol/L [1.4 mg/dL]), and a normal-appearing contralateral kidney who underwent radical or partial nephrectomy. Of these, 26% were found to have preexisting stage 3 chronic kidney disease (glomerular filtration rate < 60 mL/min/1.73 m2 as calculated using the Modification of Diet in Renal Disease equation). Additionally, 65% of patients treated with radical nephrectomy were found to have stage 3 chronic kidney disease after surgery vs 20% of patients managed with partial nephrectomy.
The misconception remains that the risk of chronic kidney disease after radical nephrectomy is insignificant, since the risk is low in renal transplant donors.19 However, renal transplant donors undergo stringent screening to ensure that their general health is good and that their renal function is robust, both of which are not true in many patients with small renal masses, particularly if they are elderly.
The overuse of radical nephrectomy is worrisome in light of the potential implications of chronic kidney disease, such as increased risk of morbid cardiovascular events and elevated mortality rates. Many experts believe that over-treatment of small renal masses may have contributed to the paradoxical increase in overall mortality rates observed with radical nephrectomy in some studies.4
Although radical nephrectomy remains an important treatment for locally advanced renal cell carcinoma, it should be performed for small renal masses only if nephron-sparing surgery is not feasible (Table 2).
Partial nephrectomy: The new gold standard for most patients
Over the last 5 years, greater emphasis has been placed on lessening the risk of chronic kidney disease in the management of all urologic conditions, including small renal masses.
The overuse of radical nephrectomy prompted the American Urological Association to commission a panel to provide guidelines for the management of clinical stage T1 renal masses.17 After an extensive review and rigorous meta-analysis, the panel concluded that partial nephrectomy is the gold standard for most patients (Table 1, Table 2).
Partial nephrectomy involves excision of the tumor with a small margin of normal tissue, preserving as much functional renal parenchyma as possible, followed by closure of the collecting system, suture ligation of any transected vessels, and reapproximation of the capsule. Tumor excision is usually performed during temporary occlusion of the renal vasculature, allowing for a bloodless field. Regional hypothermia (cold ischemia) can also be used to minimize ischemic injury.
Contemporary series have documented that partial and radical nephrectomy have comparable oncologic efficacy for patients with small renal masses.20,21 Local recurrence rates are only 1% to 2% with partial nephrectomy, and 5- and 10-year cancer-specific survival rates of 96% and 90% have been reported.22
Furthermore, some studies have shown that patients undergoing partial nephrectomy have higher overall survival rates than those managed with radical nephrectomy—perhaps in part due to greater preservation of renal function and a lower incidence of subsequent chronic kidney disease.23,24 At Cleveland Clinic, we are now studying the determinants of ultimate renal function after partial nephrectomy in an effort to minimize ischemic injury and optimize this technique.25
Complications. Partial nephrectomy does have a potential downside in that it carries a higher risk of urologic complications such as urine leak and postoperative hemorrhage, which is not surprising because it requires a reconstruction that must heal. In a recent meta-analysis, urologic complications occurred in 6.3% patients who underwent open partial nephrectomy and in 9.0% of patients who underwent laparoscopic partial nephrectomy.17 Fortunately, most complications associated with partial nephrectomy can be managed with conservative measures.
Postoperative bleeding occurs in about 1% to 2% of patients and is the most serious complication. However, it is typically managed with superselective embolization, which has a high success rate and facilitates renal preservation.
Urine leak occurs in about 3% to 5% of cases and almost always resolves with prolonged drainage, occasionally complemented with a ureteral stent to promote antegrade drainage.
A new refinement, robotic-assisted partial nephrectomy promises to reduce the morbidity of this procedure. This approach takes less time to learn than standard laparoscopic surgery and has expanded the indications for minimally invasive partial nephrectomy, although more-difficult cases are still better done through a traditional, open surgical approach.
Thermal ablation: Another minimally invasive option
Cryoablation and radiofrequency ablation (collectively called thermal ablation) have recently emerged as alternate minimally invasive treatments for small renal masses. They are appealing options for patients with small renal tumors (< 3.5 cm) who have significant comorbidities but still prefer a proactive approach. They can also be considered as salvage procedures in patients with local recurrence after partial nephrectomy or in select patients with multifocal disease.
Both procedures can be performed percutaneously or laparoscopically, offering the potential for rapid convalescence and reduced morbidity.26,27 A laparoscopic approach is necessary to mobilize the tumor from adjacent organs if they are juxtaposed, whereas a percutaneous approach is less invasive and is better suited for posterior renal masses.28 Renal mass sampling should be performed in these patients before treatment to define the histology and to guide surveillance and should be repeated postoperatively if there is suspicion of local recurrence based on imaging.
Cryoablation destroys tumor cells through rapid cycles of freezing to less than −20°C (−4°F) and thawing, which can be monitored in real time via thermocoupling (ie, a thermometer microprobe strategically placed outside the tumor to ensure that lethal temperatures are extended beyond the edge of the tumor) or via ultrasonography, or both. Treatment is continued until the “ice ball” extends about 1 cm beyond the edge of the tumor.
Initial series reported local tumor control rates in the range of 90% to 95%; however, follow-up was very limited.29 In a more robust single-institution experience,30 renal cryoablation demonstrated 5-year cancer-specific and recurrence-free survival rates of 93% and 83%, respectively, substantially lower than what would be expected with surgical excision in a similar patient population.
Another concern with cryoablation is that options are limited for surgical salvage if the initial treatment fails. Nguyen and Campbell31 reported that partial nephrectomy and minimally invasive surgery were often precluded in this situation because of the extensive fibrotic reaction caused by the prior treatment. If cryoablation fails, surgical salvage thus often requires open, radical surgery.
Radiofrequency ablation produces tumor coagulation via protein denaturation and disruption of cell membranes after heating tissues to temperatures above 50°C (122°F) for 4 to 6 minutes.32 One of its disadvantages is that one cannot monitor treatment progress in real time, as there is no identifiable change in tissue appearance analagous to the ice ball that is seen with cryoablation.
Although the outcomes of radiofrequency ablation are less robust than those of cryoablation, most studies suggest that local control is achieved in 80% to 90% of cases based on radiographic loss of enhancement after treatment.17,30,33 A recent meta-analysis comparing these treatments found that lesions treated with radiofrequency ablation had a significantly higher rate of local tumor progression than those treated with cryoablation (12.3% vs 4.7%, P < .0001).34 Both of these local recurrence rates are substantially higher than that seen after surgical excision, despite much shorter follow-up after thermal ablation.
Tempered enthusiasm. Because thermal ablation has been developed relatively recently, its long-term outcomes and treatment efficacy have not been well established, and current studies have confirmed higher local recurrence rates with thermal ablation than with surgical excision (Table 1). Furthermore, there are significant deficiencies in the literature about thermal ablation, including limited follow-up, lack of pathologic confirmation, and controversies regarding histologic or radiologic definitions of success (Table 2).
Although current enthusiasm for thermal ablation has been tempered by suboptimal results, further refinement in technique and acknowledgment of its limitations will help to define appropriate candidates for these treatments.
Active surveillance for select patients
In select patients with extensive medical comorbidities or short life expectancy, the risks associated with proactive management may outweigh the benefits, especially considering the indolent nature of many small renal masses. In such patients, active surveillance is reasonable.
A recent meta-analysis found that most small enhancing renal masses grew relatively slowly (median 0.28 cm/year) and posed a low risk of metastasis (1%–2%).17,22 Furthermore, almost all renal lesions that progressed to metastatic disease demonstrated rapid radiographic growth, suggesting that the radiographic growth of a renal mass under active surveillance may serve as an indicator for aggressive behavior.35
Unfortunately, the growth rates of small renal masses do not reliably predict malignancy, and one study reported that 83% of tumors without demonstrable growth were malignant.36
Studies of active surveillance to date have had several other important limitations. Many did not incorporate pathologic confirmation, so that about 20% of the tumors were actually benign, thus artificially reducing the risk of adverse outcomes.5,22,37 Furthermore, the follow-up has been short, with most studies including data for only 2 to 3 years, which is clearly inadequate for this type of malignancy.37,38 Finally, most series had significant selection bias towards small, homogenous masses. In general, small renal masses that appear to be more aggressive are treated and thus excluded from these surveillance populations (Table 2).
Another concern about active surveillance is the small but real risk of tumor progression to metastatic disease, rendering these patients incurable even with new, targeted molecular therapies. Additionally, some patients may lose their window of opportunity for nephron-sparing surgery if significant tumor growth occurs during observation, rendering partial nephrectomy unfeasible. Therefore, active surveillance is not advisable for young, otherwise healthy patients (Table 2).
In the future, advances in renal mass sampling with molecular profiling may help determine which renal lesions are less biologically aggressive and, thereby, help identify appropriate candidates for observation (Figure 2).
- Chow WH, Devesa SS. Contemporary epidemiology of renal cell cancer. Cancer J 2008; 14:288–301.
- Lane BR, Campbell SC. Management of small renal masses. AUA Update Series 2009; 28:313–324.
- Volpe A, Panzarella T, Rendon RA, Haider MA, Kondylis FI, Jewett MA. The natural history of incidentally detected small renal masses. Cancer 2004; 100:738–745.
- Hollingsworth JM, Miller DC, Daignault S, Hollenbeck BK. Rising incidence of small renal masses: a need to reassess treatment effect. J Natl Cancer Inst 2006; 98:1331–1334.
- Frank I, Blute ML, Cheville JC, Lohse CM, Weaver AL, Zincke H. Solid renal tumors: an analysis of pathological features related to tumor size. J Urol 2003; 170:2217–2220.
- Russo P. Should elective partial nephrectomy be performed for renal cell carcinoma >4 cm in size? Nat Clin Pract Urol 2008; 5:482–483.
- Thomas AA, Aron M, Hernandez AV, Lane BR, Gill IS. Laparoscopic partial nephrectomy in octogenarians. Urology 2009; 74:1042–1046.
- Thompson RH, Kurta JM, Kaag M, et al. Tumor size is associated with malignant potential in renal cell carcinoma cases. J Urol 2009; 181:2033–2036.
- Mues AC, Landman J. Small renal masses: current concepts regarding the natural history and reflections on the American Urological Association guidelines. Curr Opin Urol 2010; 20:105–110.
- Patard JJ, Bensalah K, Vincendeau S, Rioux-Leclerq N, Guillé F, Lobel B. [Correlation between the mode of presentation of renal tumors and patient survival]. Prog Urol 2003; 13:23–28.
- Rini BI, Campbell SC, Escudier B. Renal cell carcinoma. Lancet 2009; 373:1119–1132.
- Lane BR, Samplaski MK, Herts BR, Zhou M, Novick AC, Campbell SC. Renal mass biopsy—a renaissance? J Urol 2008; 179:20–27.
- Samplaski MK, Zhou M, Lane BR, Herts B, Campbell SC. Renal mass sampling: an enlightened perspective. Int J Urol 2011; 18:5–19.
- Tan MH, Rogers CG, Cooper JT, et al. Gene expression profiling of renal cell carcinoma. Clin Cancer Res 2004; 10:6315S–6321S.
- Miller DC, Hollingsworth JM, Hafez KS, Daignault S, Hollenbeck BK. Partial nephrectomy for small renal masses: an emerging quality of care concern? J Urol 2006; 175:853–857.
- Lane BR, Poggio ED, Herts BR, Novick AC, Campbell SC. Renal function assessment in the era of chronic kidney disease: renewed emphasis on renal function centered patient care. J Urol 2009; 182:435–444.
- Campbell SC, Novick AC, Belldegrun A, et al; Practice Guidelines Committee of the American Urological Association. Guideline for management of the clinical T1 renal mass. J Urol 2009; 182:1271–1279.
- Huang WC, Levey AS, Serio AM, et al. Chronic kidney disease after nephrectomy in patients with renal cortical tumours: a retrospective cohort study. Lancet Oncol 2006; 7:735–740.
- Boorjian SA, Uzzo RG. The evolving management of small renal masses. Curr Oncol Rep 2009; 11:211–217.
- Hafez KS, Fergany AF, Novick AC. Nephron sparing surgery for localized renal cell carcinoma: impact of tumor size on patient survival, tumor recurrence and TNM staging. J Urol 1999; 162:1930–1933.
- Lee CT, Katz J, Shi W, Thaler HT, Reuter VE, Russo P. Surgical management of renal tumors 4 cm. or less in a contemporary cohort. J Urol 2000; 163:730–736.
- Chawla SN, Crispen PL, Hanlon AL, Greenberg RE, Chen DY, Uzzo RG. The natural history of observed enhancing renal masses: meta-analysis and review of the world literature. J Urol 2006; 175:425–431.
- Huang WC, Elkin EB, Levey AS, Jang TL, Russo P. Partial nephrectomy versus radical nephrectomy in patients with small renal tumors—is there a difference in mortality and cardiovascular outcomes? J Urol 2009; 181:55–61.
- Thompson RH, Boorjian SA, Lohse CM, et al. Radical nephrectomy for pT1a renal masses may be associated with decreased overall survival compared with partial nephrectomy. J Urol 2008; 179:468–471.
- Thomas AA, Demirjian S, Lane BR, et al. Acute kidney injury: novel biomarkers and potential utility for patient care in urology. Urology 2011; 77:5–11.
- Hinshaw JL, Shadid AM, Nakada SY, Hedican SP, Winter TC, Lee FT. Comparison of percutaneous and laparoscopic cryoablation for the treatment of solid renal masses. AJR Am J Roentgenol 2008; 191:1159–1168.
- Sterrett SP, Nakada SY, Wingo MS, Williams SK, Leveillee RJ. Renal thermal ablative therapy. Urol Clin North Am 2008; 35:397–414.
- Hafron J, Kaouk JH. Ablative techniques for the management of kidney cancer. Nat Clin Pract Urol 2007; 4:261–269.
- Matin SF, Ahrar K. Nephron-sparing probe ablative therapy: longterm outcomes. Curr Opin Urol 2008; 18:150–156.
- Berger A, Kamoi K, Gill IS, Aron M. Cryoablation for renal tumors: current status. Curr Opin Urol 2009; 19:138–142.
- Nguyen CT, Campbell SC. Salvage of local recurrence after primary thermal ablation for small renal masses. Expert Rev Anticancer Ther 2008; 8:1899–1905.
- Goldberg SN, Gazelle GS, Mueller PR. Thermal ablation therapy for focal malignancy: a unified approach to underlying principles, techniques, and diagnostic imaging guidance. AJR Am J Roentgenol 2000; 174:323–331.
- Carraway WA, Raman JD, Cadeddu JA. Current status of renal radiofrequency ablation. Curr Opin Urol 2009; 19:143–147.
- Kunkle DA, Uzzo RG. Cryoablation or radiofrequency ablation of the small renal mass: a meta-analysis. Cancer 2008; 113:2671–2680.
- Kunkle DA, Kutikov A, Uzzo RG. Management of small renal masses. Semin Ultrasound CT MR 2009; 30:352–358.
- Kunkle DA, Crispen PL, Chen DY, Greenberg RE, Uzzo RG. Enhancing renal masses with zero net growth during active surveillance. J Urol 2007; 177:849–853.
- Kunkle DA, Egleston BL, Uzzo RG. Excise, ablate or observe: the small renal mass dilemma—a meta-analysis and review. J Urol 2008; 179:1227–1233.
- Jewett MA, Zuniga A. Renal tumor natural history: the rationale and role for active surveillance. Urol Clin North Am 2008; 35:627–634.
- Chow WH, Devesa SS. Contemporary epidemiology of renal cell cancer. Cancer J 2008; 14:288–301.
- Lane BR, Campbell SC. Management of small renal masses. AUA Update Series 2009; 28:313–324.
- Volpe A, Panzarella T, Rendon RA, Haider MA, Kondylis FI, Jewett MA. The natural history of incidentally detected small renal masses. Cancer 2004; 100:738–745.
- Hollingsworth JM, Miller DC, Daignault S, Hollenbeck BK. Rising incidence of small renal masses: a need to reassess treatment effect. J Natl Cancer Inst 2006; 98:1331–1334.
- Frank I, Blute ML, Cheville JC, Lohse CM, Weaver AL, Zincke H. Solid renal tumors: an analysis of pathological features related to tumor size. J Urol 2003; 170:2217–2220.
- Russo P. Should elective partial nephrectomy be performed for renal cell carcinoma >4 cm in size? Nat Clin Pract Urol 2008; 5:482–483.
- Thomas AA, Aron M, Hernandez AV, Lane BR, Gill IS. Laparoscopic partial nephrectomy in octogenarians. Urology 2009; 74:1042–1046.
- Thompson RH, Kurta JM, Kaag M, et al. Tumor size is associated with malignant potential in renal cell carcinoma cases. J Urol 2009; 181:2033–2036.
- Mues AC, Landman J. Small renal masses: current concepts regarding the natural history and reflections on the American Urological Association guidelines. Curr Opin Urol 2010; 20:105–110.
- Patard JJ, Bensalah K, Vincendeau S, Rioux-Leclerq N, Guillé F, Lobel B. [Correlation between the mode of presentation of renal tumors and patient survival]. Prog Urol 2003; 13:23–28.
- Rini BI, Campbell SC, Escudier B. Renal cell carcinoma. Lancet 2009; 373:1119–1132.
- Lane BR, Samplaski MK, Herts BR, Zhou M, Novick AC, Campbell SC. Renal mass biopsy—a renaissance? J Urol 2008; 179:20–27.
- Samplaski MK, Zhou M, Lane BR, Herts B, Campbell SC. Renal mass sampling: an enlightened perspective. Int J Urol 2011; 18:5–19.
- Tan MH, Rogers CG, Cooper JT, et al. Gene expression profiling of renal cell carcinoma. Clin Cancer Res 2004; 10:6315S–6321S.
- Miller DC, Hollingsworth JM, Hafez KS, Daignault S, Hollenbeck BK. Partial nephrectomy for small renal masses: an emerging quality of care concern? J Urol 2006; 175:853–857.
- Lane BR, Poggio ED, Herts BR, Novick AC, Campbell SC. Renal function assessment in the era of chronic kidney disease: renewed emphasis on renal function centered patient care. J Urol 2009; 182:435–444.
- Campbell SC, Novick AC, Belldegrun A, et al; Practice Guidelines Committee of the American Urological Association. Guideline for management of the clinical T1 renal mass. J Urol 2009; 182:1271–1279.
- Huang WC, Levey AS, Serio AM, et al. Chronic kidney disease after nephrectomy in patients with renal cortical tumours: a retrospective cohort study. Lancet Oncol 2006; 7:735–740.
- Boorjian SA, Uzzo RG. The evolving management of small renal masses. Curr Oncol Rep 2009; 11:211–217.
- Hafez KS, Fergany AF, Novick AC. Nephron sparing surgery for localized renal cell carcinoma: impact of tumor size on patient survival, tumor recurrence and TNM staging. J Urol 1999; 162:1930–1933.
- Lee CT, Katz J, Shi W, Thaler HT, Reuter VE, Russo P. Surgical management of renal tumors 4 cm. or less in a contemporary cohort. J Urol 2000; 163:730–736.
- Chawla SN, Crispen PL, Hanlon AL, Greenberg RE, Chen DY, Uzzo RG. The natural history of observed enhancing renal masses: meta-analysis and review of the world literature. J Urol 2006; 175:425–431.
- Huang WC, Elkin EB, Levey AS, Jang TL, Russo P. Partial nephrectomy versus radical nephrectomy in patients with small renal tumors—is there a difference in mortality and cardiovascular outcomes? J Urol 2009; 181:55–61.
- Thompson RH, Boorjian SA, Lohse CM, et al. Radical nephrectomy for pT1a renal masses may be associated with decreased overall survival compared with partial nephrectomy. J Urol 2008; 179:468–471.
- Thomas AA, Demirjian S, Lane BR, et al. Acute kidney injury: novel biomarkers and potential utility for patient care in urology. Urology 2011; 77:5–11.
- Hinshaw JL, Shadid AM, Nakada SY, Hedican SP, Winter TC, Lee FT. Comparison of percutaneous and laparoscopic cryoablation for the treatment of solid renal masses. AJR Am J Roentgenol 2008; 191:1159–1168.
- Sterrett SP, Nakada SY, Wingo MS, Williams SK, Leveillee RJ. Renal thermal ablative therapy. Urol Clin North Am 2008; 35:397–414.
- Hafron J, Kaouk JH. Ablative techniques for the management of kidney cancer. Nat Clin Pract Urol 2007; 4:261–269.
- Matin SF, Ahrar K. Nephron-sparing probe ablative therapy: longterm outcomes. Curr Opin Urol 2008; 18:150–156.
- Berger A, Kamoi K, Gill IS, Aron M. Cryoablation for renal tumors: current status. Curr Opin Urol 2009; 19:138–142.
- Nguyen CT, Campbell SC. Salvage of local recurrence after primary thermal ablation for small renal masses. Expert Rev Anticancer Ther 2008; 8:1899–1905.
- Goldberg SN, Gazelle GS, Mueller PR. Thermal ablation therapy for focal malignancy: a unified approach to underlying principles, techniques, and diagnostic imaging guidance. AJR Am J Roentgenol 2000; 174:323–331.
- Carraway WA, Raman JD, Cadeddu JA. Current status of renal radiofrequency ablation. Curr Opin Urol 2009; 19:143–147.
- Kunkle DA, Uzzo RG. Cryoablation or radiofrequency ablation of the small renal mass: a meta-analysis. Cancer 2008; 113:2671–2680.
- Kunkle DA, Kutikov A, Uzzo RG. Management of small renal masses. Semin Ultrasound CT MR 2009; 30:352–358.
- Kunkle DA, Crispen PL, Chen DY, Greenberg RE, Uzzo RG. Enhancing renal masses with zero net growth during active surveillance. J Urol 2007; 177:849–853.
- Kunkle DA, Egleston BL, Uzzo RG. Excise, ablate or observe: the small renal mass dilemma—a meta-analysis and review. J Urol 2008; 179:1227–1233.
- Jewett MA, Zuniga A. Renal tumor natural history: the rationale and role for active surveillance. Urol Clin North Am 2008; 35:627–634.
KEY POINTS
- Small renal masses are a heterogeneous group of tumors, and only 20% are aggressive renal cell carcinoma.
- In general, nephron-sparing treatments are preferred to avoid chronic kidney disease, which often occurs after radical nephrectomy.
- Thermal ablation and active surveillance are valid treatment strategies in select patients who are not optimal surgical candidates or who have limited life expectancy.
Short-Term ADT with Radiotherapy Ups Prostate Cancer Survival
Adding short-term androgen-deprivation therapy before and during conventional radiotherapy for early localized prostate cancer confers a modest but significant increase in 10-year survival, according to a new report in the July 14 issue of the New England Journal of Medicine.
The strategy also halves disease-specific 10-year mortality, reduces the rate of biochemical failure (recurrence of elevated PSA), cuts the incidence of distant metastases, and decreases the rate of positive findings on repeat prostate biopsy after 2 years, said Dr. Christopher U. Jones of Radiological Associates of Sacramento and his associates in this Radiation Therapy Oncology Group (RTOG) phase III clinical trial.
These benefits were most pronounced for men deemed to be at intermediate risk at diagnosis, they noted.
The RTOG initiated the international randomized trial because little is known about the role of short-term androgen-deprivation therapy (ADT) for nonbulky localized tumors. Study subjects comprised 1,979 men with stage T1b, T1c, T2a, or T2b prostate adenocarcinomas and an initial PSA level of 20 ng per milliliter or lower.
Patients were randomly assigned to standard radiotherapy alone (992 subjects) or radiotherapy plus three-times-daily flutamide and either subcutaneous goserelin or intramuscular leuprolide beginning 2 months before initiation of radiotherapy and continuing through 2 months of radiotherapy (987 subjects).
The primary end point was overall survival after a sufficiently long interval had passed to allow for recurrence of this often indolent cancer. The 10-year overall survival was 62% with added ADT, compared with 57% with radiotherapy alone.
The 10-year disease-specific mortality was 4% with combined therapy and 8% with radiotherapy alone. The 10-year rate of biochemical failure was 26% with combined therapy and 41% with radiotherapy alone. The 10-year cumulative incidence of distant metastases was 6% with combined therapy and 8% with radiotherapy alone.
Approximately 45% of the study population underwent repeat prostate biopsy after 2 years. Persistent cancer was detected in 20% of the specimens from men who had received radiotherapy plus ADT, compared with 39% of the men who had received radiotherapy alone.
A subgroup analysis showed that adding ADT to radiotherapy was most beneficial for men who had been considered to be at intermediate risk at baseline; they comprised slightly more than half of the study subjects. In this subgroup of 524 men who received combination therapy, 10-year overall survival was 61% (vs. 54% in the 544 intermediate-risk men who received radiotherapy alone) and 10-year disease-specific mortality was 3% (vs. 10%).
Low-risk men did not show these benefits when ADT was added to radiotherapy, but ADT did significantly decrease the incidence of biochemical failure and the rate of positive results on repeat biopsy in low-risk men. "It is conceivable that in patients with indolent disease, longer follow-up is required to show a benefit with respect to the disease-specific mortality and overall survival rates," Dr. Jones and his colleagues said (N. Engl. J. Med. 2011;365:107-18).
For the small number of subjects (11% of both study groups) considered to be at high risk at baseline, adding short-term ADT to radiotherapy did not appear to be beneficial. This comparison, however, may have been underpowered. It also may be that, as previous clinical trials have suggested, more than 4 months of ADT is required for maximum benefit in this population, the investigators added.
In all, 395 of the study subjects were black, and black men showed similar benefits from short-term ADT as did white men. Adding ADT decreased the 10-year disease-specific mortality from 7% to 5% and cut the 10-year rate of biochemical failure from 40% to 19% in black men. Overall survival was worse among black men compared with white, but disease-specific mortality was similar.
Acute and late radiation-induced toxic effects were similar between subjects who received radiotherapy alone and those who received radiotherapy plus ADT. The rate of grade 3 or higher toxic effects related to ADT was less than 5%.
Given that the addition of ADT may not be as beneficial for low-risk patients, the treatment’s toxic effects, which do affect quality of life, may tip the balance against using this approach in low-risk men. Hot flashes and erectile dysfunction were more common with ADT, and previous studies have suggested that such erectile dysfunction may be less responsive to interventions than after radiotherapy alone. Moreover, other studies have reported that even short-term ADT can cause measurable muscle loss, fat accumulation, decreased insulin sensitivity, and increases in cholesterol and triglyceride levels, Dr. Jones and his associates said.
They noted that radiotherapy techniques have changed somewhat since this study was initiated, and intensity-modulated radiotherapy, low-dose-rate brachytherapy, and high-dose-rate brachytherapy now allow "the safe delivery of higher doses of radiation than was possible when this study was conducted." The value of adding short-term ADT to these techniques is not yet known but is currently being studied in another RTOG clinical trial, they said.
The study was supported by the National Cancer Institute and no commercial support was provided. Dr. Jones’ associates reported ties to Amgen, Ferring, GlaxoSmithKline, Eli Lilly, Calypso Medical, and Varian.
The findings by Dr. Christopher U. Jones and his colleagues make it seem reasonable to conclude that hormonal therapy is not indicated in men with low-risk prostate cancer, said Dr. Anthony V. D’Amico.
However, further study is needed to determine whether it may be worthwhile in men deemed low risk who have one adverse factor such as less than 50% positive findings on prostate biopsy, perineural invasion, or a PSA velocity of more than 2 ng/mL per year.
The combined regimen must be evaluated more closely in this patient subgroup and the subgroup of men who are considered to be high risk at baseline, whose numbers may have been too small in this study to allow definitive conclusions to be reached, he wrote.
Dr. D’Amico is with the department of radiation oncology at Brigham and Women’s Hospital and the Dana-Farber Cancer Institute, Boston. He reported no financial conflicts of interest. These remarks were adapted from his editorial accompanying Dr. Jones’ report (N. Engl. J. Med. 2011;365:169-70)..
The findings by Dr. Christopher U. Jones and his colleagues make it seem reasonable to conclude that hormonal therapy is not indicated in men with low-risk prostate cancer, said Dr. Anthony V. D’Amico.
However, further study is needed to determine whether it may be worthwhile in men deemed low risk who have one adverse factor such as less than 50% positive findings on prostate biopsy, perineural invasion, or a PSA velocity of more than 2 ng/mL per year.
The combined regimen must be evaluated more closely in this patient subgroup and the subgroup of men who are considered to be high risk at baseline, whose numbers may have been too small in this study to allow definitive conclusions to be reached, he wrote.
Dr. D’Amico is with the department of radiation oncology at Brigham and Women’s Hospital and the Dana-Farber Cancer Institute, Boston. He reported no financial conflicts of interest. These remarks were adapted from his editorial accompanying Dr. Jones’ report (N. Engl. J. Med. 2011;365:169-70)..
The findings by Dr. Christopher U. Jones and his colleagues make it seem reasonable to conclude that hormonal therapy is not indicated in men with low-risk prostate cancer, said Dr. Anthony V. D’Amico.
However, further study is needed to determine whether it may be worthwhile in men deemed low risk who have one adverse factor such as less than 50% positive findings on prostate biopsy, perineural invasion, or a PSA velocity of more than 2 ng/mL per year.
The combined regimen must be evaluated more closely in this patient subgroup and the subgroup of men who are considered to be high risk at baseline, whose numbers may have been too small in this study to allow definitive conclusions to be reached, he wrote.
Dr. D’Amico is with the department of radiation oncology at Brigham and Women’s Hospital and the Dana-Farber Cancer Institute, Boston. He reported no financial conflicts of interest. These remarks were adapted from his editorial accompanying Dr. Jones’ report (N. Engl. J. Med. 2011;365:169-70)..
Adding short-term androgen-deprivation therapy before and during conventional radiotherapy for early localized prostate cancer confers a modest but significant increase in 10-year survival, according to a new report in the July 14 issue of the New England Journal of Medicine.
The strategy also halves disease-specific 10-year mortality, reduces the rate of biochemical failure (recurrence of elevated PSA), cuts the incidence of distant metastases, and decreases the rate of positive findings on repeat prostate biopsy after 2 years, said Dr. Christopher U. Jones of Radiological Associates of Sacramento and his associates in this Radiation Therapy Oncology Group (RTOG) phase III clinical trial.
These benefits were most pronounced for men deemed to be at intermediate risk at diagnosis, they noted.
The RTOG initiated the international randomized trial because little is known about the role of short-term androgen-deprivation therapy (ADT) for nonbulky localized tumors. Study subjects comprised 1,979 men with stage T1b, T1c, T2a, or T2b prostate adenocarcinomas and an initial PSA level of 20 ng per milliliter or lower.
Patients were randomly assigned to standard radiotherapy alone (992 subjects) or radiotherapy plus three-times-daily flutamide and either subcutaneous goserelin or intramuscular leuprolide beginning 2 months before initiation of radiotherapy and continuing through 2 months of radiotherapy (987 subjects).
The primary end point was overall survival after a sufficiently long interval had passed to allow for recurrence of this often indolent cancer. The 10-year overall survival was 62% with added ADT, compared with 57% with radiotherapy alone.
The 10-year disease-specific mortality was 4% with combined therapy and 8% with radiotherapy alone. The 10-year rate of biochemical failure was 26% with combined therapy and 41% with radiotherapy alone. The 10-year cumulative incidence of distant metastases was 6% with combined therapy and 8% with radiotherapy alone.
Approximately 45% of the study population underwent repeat prostate biopsy after 2 years. Persistent cancer was detected in 20% of the specimens from men who had received radiotherapy plus ADT, compared with 39% of the men who had received radiotherapy alone.
A subgroup analysis showed that adding ADT to radiotherapy was most beneficial for men who had been considered to be at intermediate risk at baseline; they comprised slightly more than half of the study subjects. In this subgroup of 524 men who received combination therapy, 10-year overall survival was 61% (vs. 54% in the 544 intermediate-risk men who received radiotherapy alone) and 10-year disease-specific mortality was 3% (vs. 10%).
Low-risk men did not show these benefits when ADT was added to radiotherapy, but ADT did significantly decrease the incidence of biochemical failure and the rate of positive results on repeat biopsy in low-risk men. "It is conceivable that in patients with indolent disease, longer follow-up is required to show a benefit with respect to the disease-specific mortality and overall survival rates," Dr. Jones and his colleagues said (N. Engl. J. Med. 2011;365:107-18).
For the small number of subjects (11% of both study groups) considered to be at high risk at baseline, adding short-term ADT to radiotherapy did not appear to be beneficial. This comparison, however, may have been underpowered. It also may be that, as previous clinical trials have suggested, more than 4 months of ADT is required for maximum benefit in this population, the investigators added.
In all, 395 of the study subjects were black, and black men showed similar benefits from short-term ADT as did white men. Adding ADT decreased the 10-year disease-specific mortality from 7% to 5% and cut the 10-year rate of biochemical failure from 40% to 19% in black men. Overall survival was worse among black men compared with white, but disease-specific mortality was similar.
Acute and late radiation-induced toxic effects were similar between subjects who received radiotherapy alone and those who received radiotherapy plus ADT. The rate of grade 3 or higher toxic effects related to ADT was less than 5%.
Given that the addition of ADT may not be as beneficial for low-risk patients, the treatment’s toxic effects, which do affect quality of life, may tip the balance against using this approach in low-risk men. Hot flashes and erectile dysfunction were more common with ADT, and previous studies have suggested that such erectile dysfunction may be less responsive to interventions than after radiotherapy alone. Moreover, other studies have reported that even short-term ADT can cause measurable muscle loss, fat accumulation, decreased insulin sensitivity, and increases in cholesterol and triglyceride levels, Dr. Jones and his associates said.
They noted that radiotherapy techniques have changed somewhat since this study was initiated, and intensity-modulated radiotherapy, low-dose-rate brachytherapy, and high-dose-rate brachytherapy now allow "the safe delivery of higher doses of radiation than was possible when this study was conducted." The value of adding short-term ADT to these techniques is not yet known but is currently being studied in another RTOG clinical trial, they said.
The study was supported by the National Cancer Institute and no commercial support was provided. Dr. Jones’ associates reported ties to Amgen, Ferring, GlaxoSmithKline, Eli Lilly, Calypso Medical, and Varian.
Adding short-term androgen-deprivation therapy before and during conventional radiotherapy for early localized prostate cancer confers a modest but significant increase in 10-year survival, according to a new report in the July 14 issue of the New England Journal of Medicine.
The strategy also halves disease-specific 10-year mortality, reduces the rate of biochemical failure (recurrence of elevated PSA), cuts the incidence of distant metastases, and decreases the rate of positive findings on repeat prostate biopsy after 2 years, said Dr. Christopher U. Jones of Radiological Associates of Sacramento and his associates in this Radiation Therapy Oncology Group (RTOG) phase III clinical trial.
These benefits were most pronounced for men deemed to be at intermediate risk at diagnosis, they noted.
The RTOG initiated the international randomized trial because little is known about the role of short-term androgen-deprivation therapy (ADT) for nonbulky localized tumors. Study subjects comprised 1,979 men with stage T1b, T1c, T2a, or T2b prostate adenocarcinomas and an initial PSA level of 20 ng per milliliter or lower.
Patients were randomly assigned to standard radiotherapy alone (992 subjects) or radiotherapy plus three-times-daily flutamide and either subcutaneous goserelin or intramuscular leuprolide beginning 2 months before initiation of radiotherapy and continuing through 2 months of radiotherapy (987 subjects).
The primary end point was overall survival after a sufficiently long interval had passed to allow for recurrence of this often indolent cancer. The 10-year overall survival was 62% with added ADT, compared with 57% with radiotherapy alone.
The 10-year disease-specific mortality was 4% with combined therapy and 8% with radiotherapy alone. The 10-year rate of biochemical failure was 26% with combined therapy and 41% with radiotherapy alone. The 10-year cumulative incidence of distant metastases was 6% with combined therapy and 8% with radiotherapy alone.
Approximately 45% of the study population underwent repeat prostate biopsy after 2 years. Persistent cancer was detected in 20% of the specimens from men who had received radiotherapy plus ADT, compared with 39% of the men who had received radiotherapy alone.
A subgroup analysis showed that adding ADT to radiotherapy was most beneficial for men who had been considered to be at intermediate risk at baseline; they comprised slightly more than half of the study subjects. In this subgroup of 524 men who received combination therapy, 10-year overall survival was 61% (vs. 54% in the 544 intermediate-risk men who received radiotherapy alone) and 10-year disease-specific mortality was 3% (vs. 10%).
Low-risk men did not show these benefits when ADT was added to radiotherapy, but ADT did significantly decrease the incidence of biochemical failure and the rate of positive results on repeat biopsy in low-risk men. "It is conceivable that in patients with indolent disease, longer follow-up is required to show a benefit with respect to the disease-specific mortality and overall survival rates," Dr. Jones and his colleagues said (N. Engl. J. Med. 2011;365:107-18).
For the small number of subjects (11% of both study groups) considered to be at high risk at baseline, adding short-term ADT to radiotherapy did not appear to be beneficial. This comparison, however, may have been underpowered. It also may be that, as previous clinical trials have suggested, more than 4 months of ADT is required for maximum benefit in this population, the investigators added.
In all, 395 of the study subjects were black, and black men showed similar benefits from short-term ADT as did white men. Adding ADT decreased the 10-year disease-specific mortality from 7% to 5% and cut the 10-year rate of biochemical failure from 40% to 19% in black men. Overall survival was worse among black men compared with white, but disease-specific mortality was similar.
Acute and late radiation-induced toxic effects were similar between subjects who received radiotherapy alone and those who received radiotherapy plus ADT. The rate of grade 3 or higher toxic effects related to ADT was less than 5%.
Given that the addition of ADT may not be as beneficial for low-risk patients, the treatment’s toxic effects, which do affect quality of life, may tip the balance against using this approach in low-risk men. Hot flashes and erectile dysfunction were more common with ADT, and previous studies have suggested that such erectile dysfunction may be less responsive to interventions than after radiotherapy alone. Moreover, other studies have reported that even short-term ADT can cause measurable muscle loss, fat accumulation, decreased insulin sensitivity, and increases in cholesterol and triglyceride levels, Dr. Jones and his associates said.
They noted that radiotherapy techniques have changed somewhat since this study was initiated, and intensity-modulated radiotherapy, low-dose-rate brachytherapy, and high-dose-rate brachytherapy now allow "the safe delivery of higher doses of radiation than was possible when this study was conducted." The value of adding short-term ADT to these techniques is not yet known but is currently being studied in another RTOG clinical trial, they said.
The study was supported by the National Cancer Institute and no commercial support was provided. Dr. Jones’ associates reported ties to Amgen, Ferring, GlaxoSmithKline, Eli Lilly, Calypso Medical, and Varian.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Major Finding: Adding short-term androgen-deprivation therapy to standard radiotherapy raised overall survival at 10 years from 57% to 62%, cut disease-specific mortality from 8% to 4%, lowered biochemical failure from 41% to 26%, and decreased the incidence of distant metastases from 8% to 6%.
Data Source: An international phase III randomized controlled trial comparing conventional radiotherapy with radiotherapy plus short-term ADT in 1,979 men with early localized prostate cancer who were followed for a minimum of 9 years.
Disclosures: The study was supported by the National Cancer Institute and no commercial support was provided. Dr. Jones’ associates reported ties to Amgen, Ferring, GlaxoSmithKline, Eli Lilly, Calypso Medical, and Varian.
Discordant Antibiotic Therapy for UTI Stretches Hospital Stays
DENVER – Discordant antibiotic therapy occurred in 11% of a large series of children admitted for urinary tract infection at five major freestanding children’s hospitals.
Antibiotic discordance occurs when the causative organism demonstrates in vitro nonsusceptibility to the empiric antibiotic therapy that was administered before the urine culture results became available. In this five-hospital study, discordant antibiotic therapy was associated with a significantly increased length of stay, Dr. Karen E. Jerardi reported at the annual meeting of the Pediatric Academic Societies.
"For most of the cases of antibiotic discordance, the antibiotics were clinically appropriate in the setting of presumed [urinary tract infection], but the bacteria themselves were more resistant," said Dr. Jerardi of Cincinnati Children’s Hospital.
The implication is: Know your local uropathogen resistance patterns and align the initial empiric antibiotic therapy accordingly, she said.
The study involved 192 patients aged 3 days to 18 years who were hospitalized for urinary tract infection (UTI), with a median 3-day length of stay. The major uropathogens identified were Escherichia coli in 66% of cases, Klebsiella species in 11%, Enterococcus species in 6%, and Pseudomonas species in 5%. Mixed-organism UTIs accounted for 5% of the total.
The most common initial antibiotics were third-generation cephalosporins in 39% of cases, followed by ampicillin plus a third- or fourth-generation cephalosporin in 16%, and ampicillin plus gentamicin in 11%, with other agents being employed in the low single digits.
Antibiotic discordance was most frequent in UTIs caused by Klebsiella species, with a 7% rate. The other causative organisms where antibiotic discordance was common were mixed-organism infections, with a 5% antibiotic discordance rate, and E. coli and enterococcus, each with a 3% rate.
There were no significant differences between the concordant and discordant groups in terms of patient age, sex, chronic care conditions, presence of vesicoureteral reflux, or the use of prophylactic antibiotics. In a multivariate linear regression analysis adjusted for these factors, length of stay was a median 1.8 days shorter for patients treated initially with a concordant antibiotic. For the two-thirds of patients with an E. coli UTI, concordant antibiotic therapy was associated with a 3.1-day shorter stay.
As UTI is a common condition – accounting for 2% of all pediatric hospitalizations – selecting an initial antibiotic based on local uropathogen resistance patterns could result in significant cost savings as well as reduced exposure to unnecessary antibiotics, Dr. Jerardi observed.
She said she had no relevant financial disclosures.
Antibiotic discordance, UTI, Dr. Karen E. Jerardi, the Pediatric Academic Societies, bacteria, uropathogen resistance patterns, empiric antibiotic therapy, uropathogens, Escherichia coli, Klebsiella, Enterococcus, Pseudomonas, cephalosporins, ampicillin,
DENVER – Discordant antibiotic therapy occurred in 11% of a large series of children admitted for urinary tract infection at five major freestanding children’s hospitals.
Antibiotic discordance occurs when the causative organism demonstrates in vitro nonsusceptibility to the empiric antibiotic therapy that was administered before the urine culture results became available. In this five-hospital study, discordant antibiotic therapy was associated with a significantly increased length of stay, Dr. Karen E. Jerardi reported at the annual meeting of the Pediatric Academic Societies.
"For most of the cases of antibiotic discordance, the antibiotics were clinically appropriate in the setting of presumed [urinary tract infection], but the bacteria themselves were more resistant," said Dr. Jerardi of Cincinnati Children’s Hospital.
The implication is: Know your local uropathogen resistance patterns and align the initial empiric antibiotic therapy accordingly, she said.
The study involved 192 patients aged 3 days to 18 years who were hospitalized for urinary tract infection (UTI), with a median 3-day length of stay. The major uropathogens identified were Escherichia coli in 66% of cases, Klebsiella species in 11%, Enterococcus species in 6%, and Pseudomonas species in 5%. Mixed-organism UTIs accounted for 5% of the total.
The most common initial antibiotics were third-generation cephalosporins in 39% of cases, followed by ampicillin plus a third- or fourth-generation cephalosporin in 16%, and ampicillin plus gentamicin in 11%, with other agents being employed in the low single digits.
Antibiotic discordance was most frequent in UTIs caused by Klebsiella species, with a 7% rate. The other causative organisms where antibiotic discordance was common were mixed-organism infections, with a 5% antibiotic discordance rate, and E. coli and enterococcus, each with a 3% rate.
There were no significant differences between the concordant and discordant groups in terms of patient age, sex, chronic care conditions, presence of vesicoureteral reflux, or the use of prophylactic antibiotics. In a multivariate linear regression analysis adjusted for these factors, length of stay was a median 1.8 days shorter for patients treated initially with a concordant antibiotic. For the two-thirds of patients with an E. coli UTI, concordant antibiotic therapy was associated with a 3.1-day shorter stay.
As UTI is a common condition – accounting for 2% of all pediatric hospitalizations – selecting an initial antibiotic based on local uropathogen resistance patterns could result in significant cost savings as well as reduced exposure to unnecessary antibiotics, Dr. Jerardi observed.
She said she had no relevant financial disclosures.
DENVER – Discordant antibiotic therapy occurred in 11% of a large series of children admitted for urinary tract infection at five major freestanding children’s hospitals.
Antibiotic discordance occurs when the causative organism demonstrates in vitro nonsusceptibility to the empiric antibiotic therapy that was administered before the urine culture results became available. In this five-hospital study, discordant antibiotic therapy was associated with a significantly increased length of stay, Dr. Karen E. Jerardi reported at the annual meeting of the Pediatric Academic Societies.
"For most of the cases of antibiotic discordance, the antibiotics were clinically appropriate in the setting of presumed [urinary tract infection], but the bacteria themselves were more resistant," said Dr. Jerardi of Cincinnati Children’s Hospital.
The implication is: Know your local uropathogen resistance patterns and align the initial empiric antibiotic therapy accordingly, she said.
The study involved 192 patients aged 3 days to 18 years who were hospitalized for urinary tract infection (UTI), with a median 3-day length of stay. The major uropathogens identified were Escherichia coli in 66% of cases, Klebsiella species in 11%, Enterococcus species in 6%, and Pseudomonas species in 5%. Mixed-organism UTIs accounted for 5% of the total.
The most common initial antibiotics were third-generation cephalosporins in 39% of cases, followed by ampicillin plus a third- or fourth-generation cephalosporin in 16%, and ampicillin plus gentamicin in 11%, with other agents being employed in the low single digits.
Antibiotic discordance was most frequent in UTIs caused by Klebsiella species, with a 7% rate. The other causative organisms where antibiotic discordance was common were mixed-organism infections, with a 5% antibiotic discordance rate, and E. coli and enterococcus, each with a 3% rate.
There were no significant differences between the concordant and discordant groups in terms of patient age, sex, chronic care conditions, presence of vesicoureteral reflux, or the use of prophylactic antibiotics. In a multivariate linear regression analysis adjusted for these factors, length of stay was a median 1.8 days shorter for patients treated initially with a concordant antibiotic. For the two-thirds of patients with an E. coli UTI, concordant antibiotic therapy was associated with a 3.1-day shorter stay.
As UTI is a common condition – accounting for 2% of all pediatric hospitalizations – selecting an initial antibiotic based on local uropathogen resistance patterns could result in significant cost savings as well as reduced exposure to unnecessary antibiotics, Dr. Jerardi observed.
She said she had no relevant financial disclosures.
Antibiotic discordance, UTI, Dr. Karen E. Jerardi, the Pediatric Academic Societies, bacteria, uropathogen resistance patterns, empiric antibiotic therapy, uropathogens, Escherichia coli, Klebsiella, Enterococcus, Pseudomonas, cephalosporins, ampicillin,
Antibiotic discordance, UTI, Dr. Karen E. Jerardi, the Pediatric Academic Societies, bacteria, uropathogen resistance patterns, empiric antibiotic therapy, uropathogens, Escherichia coli, Klebsiella, Enterococcus, Pseudomonas, cephalosporins, ampicillin,
FROM THE ANNUAL MEETING OF THE PEDIATRIC ACADEMIC SOCIETIES
Discordant Antibiotic Therapy for UTI Stretches Hospital Stays
DENVER – Discordant antibiotic therapy occurred in 11% of a large series of children admitted for urinary tract infection at five major freestanding children’s hospitals.
Antibiotic discordance occurs when the causative organism demonstrates in vitro nonsusceptibility to the empiric antibiotic therapy that was administered before the urine culture results became available. In this five-hospital study, discordant antibiotic therapy was associated with a significantly increased length of stay, Dr. Karen E. Jerardi reported at the annual meeting of the Pediatric Academic Societies.
"For most of the cases of antibiotic discordance, the antibiotics were clinically appropriate in the setting of presumed [urinary tract infection], but the bacteria themselves were more resistant," said Dr. Jerardi of Cincinnati Children’s Hospital.
The implication is: Know your local uropathogen resistance patterns and align the initial empiric antibiotic therapy accordingly, she said.
The study involved 192 patients aged 3 days to 18 years who were hospitalized for urinary tract infection (UTI), with a median 3-day length of stay. The major uropathogens identified were Escherichia coli in 66% of cases, Klebsiella species in 11%, Enterococcus species in 6%, and Pseudomonas species in 5%. Mixed-organism UTIs accounted for 5% of the total.
The most common initial antibiotics were third-generation cephalosporins in 39% of cases, followed by ampicillin plus a third- or fourth-generation cephalosporin in 16%, and ampicillin plus gentamicin in 11%, with other agents being employed in the low single digits.
Antibiotic discordance was most frequent in UTIs caused by Klebsiella species, with a 7% rate. The other causative organisms where antibiotic discordance was common were mixed-organism infections, with a 5% antibiotic discordance rate, and E. coli and enterococcus, each with a 3% rate.
There were no significant differences between the concordant and discordant groups in terms of patient age, sex, chronic care conditions, presence of vesicoureteral reflux, or the use of prophylactic antibiotics. In a multivariate linear regression analysis adjusted for these factors, length of stay was a median 1.8 days shorter for patients treated initially with a concordant antibiotic. For the two-thirds of patients with an E. coli UTI, concordant antibiotic therapy was associated with a 3.1-day shorter stay.
As UTI is a common condition – accounting for 2% of all pediatric hospitalizations – selecting an initial antibiotic based on local uropathogen resistance patterns could result in significant cost savings as well as reduced exposure to unnecessary antibiotics, Dr. Jerardi observed.
She said she had no relevant financial disclosures.
Antibiotic discordance, UTI, Dr. Karen E. Jerardi, the Pediatric Academic Societies, bacteria, uropathogen resistance patterns, empiric antibiotic therapy, uropathogens, Escherichia coli, Klebsiella, Enterococcus, Pseudomonas, cephalosporins, ampicillin,
DENVER – Discordant antibiotic therapy occurred in 11% of a large series of children admitted for urinary tract infection at five major freestanding children’s hospitals.
Antibiotic discordance occurs when the causative organism demonstrates in vitro nonsusceptibility to the empiric antibiotic therapy that was administered before the urine culture results became available. In this five-hospital study, discordant antibiotic therapy was associated with a significantly increased length of stay, Dr. Karen E. Jerardi reported at the annual meeting of the Pediatric Academic Societies.
"For most of the cases of antibiotic discordance, the antibiotics were clinically appropriate in the setting of presumed [urinary tract infection], but the bacteria themselves were more resistant," said Dr. Jerardi of Cincinnati Children’s Hospital.
The implication is: Know your local uropathogen resistance patterns and align the initial empiric antibiotic therapy accordingly, she said.
The study involved 192 patients aged 3 days to 18 years who were hospitalized for urinary tract infection (UTI), with a median 3-day length of stay. The major uropathogens identified were Escherichia coli in 66% of cases, Klebsiella species in 11%, Enterococcus species in 6%, and Pseudomonas species in 5%. Mixed-organism UTIs accounted for 5% of the total.
The most common initial antibiotics were third-generation cephalosporins in 39% of cases, followed by ampicillin plus a third- or fourth-generation cephalosporin in 16%, and ampicillin plus gentamicin in 11%, with other agents being employed in the low single digits.
Antibiotic discordance was most frequent in UTIs caused by Klebsiella species, with a 7% rate. The other causative organisms where antibiotic discordance was common were mixed-organism infections, with a 5% antibiotic discordance rate, and E. coli and enterococcus, each with a 3% rate.
There were no significant differences between the concordant and discordant groups in terms of patient age, sex, chronic care conditions, presence of vesicoureteral reflux, or the use of prophylactic antibiotics. In a multivariate linear regression analysis adjusted for these factors, length of stay was a median 1.8 days shorter for patients treated initially with a concordant antibiotic. For the two-thirds of patients with an E. coli UTI, concordant antibiotic therapy was associated with a 3.1-day shorter stay.
As UTI is a common condition – accounting for 2% of all pediatric hospitalizations – selecting an initial antibiotic based on local uropathogen resistance patterns could result in significant cost savings as well as reduced exposure to unnecessary antibiotics, Dr. Jerardi observed.
She said she had no relevant financial disclosures.
DENVER – Discordant antibiotic therapy occurred in 11% of a large series of children admitted for urinary tract infection at five major freestanding children’s hospitals.
Antibiotic discordance occurs when the causative organism demonstrates in vitro nonsusceptibility to the empiric antibiotic therapy that was administered before the urine culture results became available. In this five-hospital study, discordant antibiotic therapy was associated with a significantly increased length of stay, Dr. Karen E. Jerardi reported at the annual meeting of the Pediatric Academic Societies.
"For most of the cases of antibiotic discordance, the antibiotics were clinically appropriate in the setting of presumed [urinary tract infection], but the bacteria themselves were more resistant," said Dr. Jerardi of Cincinnati Children’s Hospital.
The implication is: Know your local uropathogen resistance patterns and align the initial empiric antibiotic therapy accordingly, she said.
The study involved 192 patients aged 3 days to 18 years who were hospitalized for urinary tract infection (UTI), with a median 3-day length of stay. The major uropathogens identified were Escherichia coli in 66% of cases, Klebsiella species in 11%, Enterococcus species in 6%, and Pseudomonas species in 5%. Mixed-organism UTIs accounted for 5% of the total.
The most common initial antibiotics were third-generation cephalosporins in 39% of cases, followed by ampicillin plus a third- or fourth-generation cephalosporin in 16%, and ampicillin plus gentamicin in 11%, with other agents being employed in the low single digits.
Antibiotic discordance was most frequent in UTIs caused by Klebsiella species, with a 7% rate. The other causative organisms where antibiotic discordance was common were mixed-organism infections, with a 5% antibiotic discordance rate, and E. coli and enterococcus, each with a 3% rate.
There were no significant differences between the concordant and discordant groups in terms of patient age, sex, chronic care conditions, presence of vesicoureteral reflux, or the use of prophylactic antibiotics. In a multivariate linear regression analysis adjusted for these factors, length of stay was a median 1.8 days shorter for patients treated initially with a concordant antibiotic. For the two-thirds of patients with an E. coli UTI, concordant antibiotic therapy was associated with a 3.1-day shorter stay.
As UTI is a common condition – accounting for 2% of all pediatric hospitalizations – selecting an initial antibiotic based on local uropathogen resistance patterns could result in significant cost savings as well as reduced exposure to unnecessary antibiotics, Dr. Jerardi observed.
She said she had no relevant financial disclosures.
Antibiotic discordance, UTI, Dr. Karen E. Jerardi, the Pediatric Academic Societies, bacteria, uropathogen resistance patterns, empiric antibiotic therapy, uropathogens, Escherichia coli, Klebsiella, Enterococcus, Pseudomonas, cephalosporins, ampicillin,
Antibiotic discordance, UTI, Dr. Karen E. Jerardi, the Pediatric Academic Societies, bacteria, uropathogen resistance patterns, empiric antibiotic therapy, uropathogens, Escherichia coli, Klebsiella, Enterococcus, Pseudomonas, cephalosporins, ampicillin,
FROM THE ANNUAL MEETING OF THE PEDIATRIC ACADEMIC SOCIETIES
Major Finding: Discordant antibiotic therapy occurred in 11% of children admitted for urinary tract infection.
Data Source: A series of 192 patients aged 3 days to 18 years who were hospitalized for UTI at five children’s hospitals.
Disclosures: Dr. Jerardi reported having no relevant financial disclosures.
FDA Tightens ESA Dosing Recommendations for CKD Anemia
The Food and Drug Administration on June 24 issued more conservative dosing guidelines for the use of erythropoiesis-stimulating agents to treat anemia in chronic kidney disease patients who face increased risks of cardiovascular events associated with these drugs.
The new recommendations do away with a targeted range of 10-12 g/dL in hemoglobin levels in patients with chronic kidney disease (CKD). Instead, they set ceilings of 10 to 11 g/dL, depending on whether or not the anemic patient is on dialysis.
Clinicians should "individualize dosing and use the lowest dose of ESA [erythropoiesis-stimulating agent] sufficient to reduce the need for red blood cell transfusions," the agency said. The label recommends that dosing be adjusted "as appropriate."
Based on dialysis status, the new recommendations are as follows:
• If the patient is not on dialysis, the FDA advises that clinicians "consider" starting treatment with an ESA when a patient’s hemoglobin level drops below 10 g/dL "and when certain other considerations apply," for instance, if the rate of hemoglobin decline indicates that a transfusion will likely be needed.
The recommendation "does not define how far below 10 g/dL is appropriate for an individual to initiate," the agency said. It calls on clinicians to "reduce or interrupt the dose of ESA" if the patient’s level goes above 10 g/dL.
• If the patient is on dialysis, the FDA says to start ESA treatment when the patient’s hemoglobin level goes below 10 g/dL. In this case, the threshold for reducing or interrupting the ESA dose is when the hemoglobin level "approaches or exceeds 11 g/dL."
Previously, the recommendation was to dose ESAs to achieve and maintain hemoglobin levels in the target range of 10-12 g/dL; this has been removed from ESA labels. Targeting the hemoglobin level to above 11 g/dL has been found to increase the risk of myocardial infarction, stroke, and other serious adverse cardiovascular events in patients with CKD, and "has not been shown to provide additional patient benefit," the FDA statement said.
ESAs currently available in the United States are epoetin alfa (Epogen and Procrit), and darbepoetin alfa (Aranesp). All are manufactured by Amgen; Procrit is marketed by Centecor Ortho Biotech. These agents also are approved to treat anemia associated with cancer chemotherapy.
The intention of the new dosing guidelines and revised label is to "encourage flexibility" of dosing and to reinforce the message that "serious risks have been demonstrated" when the target is above 11 g/dL, Dr. Robert Kane, acting deputy director for safety in the Division of Hematology Products, FDA Center for Drug Evaluation and Research (CDER), said during a briefing.
He pointed out that the recommendations are different for patients with CKD who are on dialysis and those not on dialysis, because the risk-benefit profile is different for these groups.
The risks of ESAs in patients with CKD have been discussed at two FDA advisory panel meetings, most recently in October 2010, when an expert panel reviewed the results of the TREAT (Trial to Reduce Cardiovascular Events with Aranesp Therapy) study of darbepoetin alfa, which found an increased risk for stroke associated with a hemoglobin target of 13.0 g/dL in CKD patients not on dialysis. The new dosing recommendations have been added to the boxed warning and other sections of the label for ESAs.
Dr. Richard Pazdur, director of the FDA’s Office of Oncology Drug Products in CDER, said that the new dosing recommendations do not directly affect the use of ESAs in people with cancer, but statements included in the warnings and precautions section of the label apply to all patients who are treated with ESAs.
Amgen issued a statement that it supports the changes and is in discussion with the FDA on what additional postmarketing studies are needed.
The FDA statement and additional information are available at http://www.fda.gov/Drugs/DrugSafety/ucm259639.htm. Adverse events associated with ESAs should be reported to the FDA’s MedWatch program at 800-332-1088 or http://www.fda.gov/medwatch/.
The Food and Drug Administration on June 24 issued more conservative dosing guidelines for the use of erythropoiesis-stimulating agents to treat anemia in chronic kidney disease patients who face increased risks of cardiovascular events associated with these drugs.
The new recommendations do away with a targeted range of 10-12 g/dL in hemoglobin levels in patients with chronic kidney disease (CKD). Instead, they set ceilings of 10 to 11 g/dL, depending on whether or not the anemic patient is on dialysis.
Clinicians should "individualize dosing and use the lowest dose of ESA [erythropoiesis-stimulating agent] sufficient to reduce the need for red blood cell transfusions," the agency said. The label recommends that dosing be adjusted "as appropriate."
Based on dialysis status, the new recommendations are as follows:
• If the patient is not on dialysis, the FDA advises that clinicians "consider" starting treatment with an ESA when a patient’s hemoglobin level drops below 10 g/dL "and when certain other considerations apply," for instance, if the rate of hemoglobin decline indicates that a transfusion will likely be needed.
The recommendation "does not define how far below 10 g/dL is appropriate for an individual to initiate," the agency said. It calls on clinicians to "reduce or interrupt the dose of ESA" if the patient’s level goes above 10 g/dL.
• If the patient is on dialysis, the FDA says to start ESA treatment when the patient’s hemoglobin level goes below 10 g/dL. In this case, the threshold for reducing or interrupting the ESA dose is when the hemoglobin level "approaches or exceeds 11 g/dL."
Previously, the recommendation was to dose ESAs to achieve and maintain hemoglobin levels in the target range of 10-12 g/dL; this has been removed from ESA labels. Targeting the hemoglobin level to above 11 g/dL has been found to increase the risk of myocardial infarction, stroke, and other serious adverse cardiovascular events in patients with CKD, and "has not been shown to provide additional patient benefit," the FDA statement said.
ESAs currently available in the United States are epoetin alfa (Epogen and Procrit), and darbepoetin alfa (Aranesp). All are manufactured by Amgen; Procrit is marketed by Centecor Ortho Biotech. These agents also are approved to treat anemia associated with cancer chemotherapy.
The intention of the new dosing guidelines and revised label is to "encourage flexibility" of dosing and to reinforce the message that "serious risks have been demonstrated" when the target is above 11 g/dL, Dr. Robert Kane, acting deputy director for safety in the Division of Hematology Products, FDA Center for Drug Evaluation and Research (CDER), said during a briefing.
He pointed out that the recommendations are different for patients with CKD who are on dialysis and those not on dialysis, because the risk-benefit profile is different for these groups.
The risks of ESAs in patients with CKD have been discussed at two FDA advisory panel meetings, most recently in October 2010, when an expert panel reviewed the results of the TREAT (Trial to Reduce Cardiovascular Events with Aranesp Therapy) study of darbepoetin alfa, which found an increased risk for stroke associated with a hemoglobin target of 13.0 g/dL in CKD patients not on dialysis. The new dosing recommendations have been added to the boxed warning and other sections of the label for ESAs.
Dr. Richard Pazdur, director of the FDA’s Office of Oncology Drug Products in CDER, said that the new dosing recommendations do not directly affect the use of ESAs in people with cancer, but statements included in the warnings and precautions section of the label apply to all patients who are treated with ESAs.
Amgen issued a statement that it supports the changes and is in discussion with the FDA on what additional postmarketing studies are needed.
The FDA statement and additional information are available at http://www.fda.gov/Drugs/DrugSafety/ucm259639.htm. Adverse events associated with ESAs should be reported to the FDA’s MedWatch program at 800-332-1088 or http://www.fda.gov/medwatch/.
The Food and Drug Administration on June 24 issued more conservative dosing guidelines for the use of erythropoiesis-stimulating agents to treat anemia in chronic kidney disease patients who face increased risks of cardiovascular events associated with these drugs.
The new recommendations do away with a targeted range of 10-12 g/dL in hemoglobin levels in patients with chronic kidney disease (CKD). Instead, they set ceilings of 10 to 11 g/dL, depending on whether or not the anemic patient is on dialysis.
Clinicians should "individualize dosing and use the lowest dose of ESA [erythropoiesis-stimulating agent] sufficient to reduce the need for red blood cell transfusions," the agency said. The label recommends that dosing be adjusted "as appropriate."
Based on dialysis status, the new recommendations are as follows:
• If the patient is not on dialysis, the FDA advises that clinicians "consider" starting treatment with an ESA when a patient’s hemoglobin level drops below 10 g/dL "and when certain other considerations apply," for instance, if the rate of hemoglobin decline indicates that a transfusion will likely be needed.
The recommendation "does not define how far below 10 g/dL is appropriate for an individual to initiate," the agency said. It calls on clinicians to "reduce or interrupt the dose of ESA" if the patient’s level goes above 10 g/dL.
• If the patient is on dialysis, the FDA says to start ESA treatment when the patient’s hemoglobin level goes below 10 g/dL. In this case, the threshold for reducing or interrupting the ESA dose is when the hemoglobin level "approaches or exceeds 11 g/dL."
Previously, the recommendation was to dose ESAs to achieve and maintain hemoglobin levels in the target range of 10-12 g/dL; this has been removed from ESA labels. Targeting the hemoglobin level to above 11 g/dL has been found to increase the risk of myocardial infarction, stroke, and other serious adverse cardiovascular events in patients with CKD, and "has not been shown to provide additional patient benefit," the FDA statement said.
ESAs currently available in the United States are epoetin alfa (Epogen and Procrit), and darbepoetin alfa (Aranesp). All are manufactured by Amgen; Procrit is marketed by Centecor Ortho Biotech. These agents also are approved to treat anemia associated with cancer chemotherapy.
The intention of the new dosing guidelines and revised label is to "encourage flexibility" of dosing and to reinforce the message that "serious risks have been demonstrated" when the target is above 11 g/dL, Dr. Robert Kane, acting deputy director for safety in the Division of Hematology Products, FDA Center for Drug Evaluation and Research (CDER), said during a briefing.
He pointed out that the recommendations are different for patients with CKD who are on dialysis and those not on dialysis, because the risk-benefit profile is different for these groups.
The risks of ESAs in patients with CKD have been discussed at two FDA advisory panel meetings, most recently in October 2010, when an expert panel reviewed the results of the TREAT (Trial to Reduce Cardiovascular Events with Aranesp Therapy) study of darbepoetin alfa, which found an increased risk for stroke associated with a hemoglobin target of 13.0 g/dL in CKD patients not on dialysis. The new dosing recommendations have been added to the boxed warning and other sections of the label for ESAs.
Dr. Richard Pazdur, director of the FDA’s Office of Oncology Drug Products in CDER, said that the new dosing recommendations do not directly affect the use of ESAs in people with cancer, but statements included in the warnings and precautions section of the label apply to all patients who are treated with ESAs.
Amgen issued a statement that it supports the changes and is in discussion with the FDA on what additional postmarketing studies are needed.
The FDA statement and additional information are available at http://www.fda.gov/Drugs/DrugSafety/ucm259639.htm. Adverse events associated with ESAs should be reported to the FDA’s MedWatch program at 800-332-1088 or http://www.fda.gov/medwatch/.
FROM THE FOOD AND DRUG ADMINISTRATION
FDA Tightens ESA Dosing Recommendations for CKD Anemia
The Food and Drug Administration on June 24 issued more conservative dosing guidelines for the use of erythropoiesis-stimulating agents to treat anemia in chronic kidney disease patients who face increased risks of cardiovascular events associated with these drugs.
The new recommendations do away with a targeted range of 10-12 g/dL in hemoglobin levels in patients with chronic kidney disease (CKD). Instead, they set ceilings of 10 to 11 g/dL, depending on whether or not the anemic patient is on dialysis.
Clinicians should "individualize dosing and use the lowest dose of ESA [erythropoiesis-stimulating agent] sufficient to reduce the need for red blood cell transfusions," the agency said. The label recommends that dosing be adjusted "as appropriate."
Based on dialysis status, the new recommendations are as follows:
• If the patient is not on dialysis, the FDA advises that clinicians "consider" starting treatment with an ESA when a patient’s hemoglobin level drops below 10 g/dL "and when certain other considerations apply," for instance, if the rate of hemoglobin decline indicates that a transfusion will likely be needed.
The recommendation "does not define how far below 10 g/dL is appropriate for an individual to initiate," the agency said. It calls on clinicians to "reduce or interrupt the dose of ESA" if the patient’s level goes above 10 g/dL.
• If the patient is on dialysis, the FDA says to start ESA treatment when the patient’s hemoglobin level goes below 10 g/dL. In this case, the threshold for reducing or interrupting the ESA dose is when the hemoglobin level "approaches or exceeds 11 g/dL."
Previously, the recommendation was to dose ESAs to achieve and maintain hemoglobin levels in the target range of 10-12 g/dL; this has been removed from ESA labels. Targeting the hemoglobin level to above 11 g/dL has been found to increase the risk of myocardial infarction, stroke, and other serious adverse cardiovascular events in patients with CKD, and "has not been shown to provide additional patient benefit," the FDA statement said.
ESAs currently available in the United States are epoetin alfa (Epogen and Procrit), and darbepoetin alfa (Aranesp). All are manufactured by Amgen; Procrit is marketed by Centecor Ortho Biotech. These agents also are approved to treat anemia associated with cancer chemotherapy.
The intention of the new dosing guidelines and revised label is to "encourage flexibility" of dosing and to reinforce the message that "serious risks have been demonstrated" when the target is above 11 g/dL, Dr. Robert Kane, acting deputy director for safety in the Division of Hematology Products, FDA Center for Drug Evaluation and Research (CDER), said during a briefing.
He pointed out that the recommendations are different for patients with CKD who are on dialysis and those not on dialysis, because the risk-benefit profile is different for these groups.
The risks of ESAs in patients with CKD have been discussed at two FDA advisory panel meetings, most recently in October 2010, when an expert panel reviewed the results of the TREAT (Trial to Reduce Cardiovascular Events with Aranesp Therapy) study of darbepoetin alfa, which found an increased risk for stroke associated with a hemoglobin target of 13.0 g/dL in CKD patients not on dialysis. The new dosing recommendations have been added to the boxed warning and other sections of the label for ESAs.
Dr. Richard Pazdur, director of the FDA’s Office of Oncology Drug Products in CDER, said that the new dosing recommendations do not directly affect the use of ESAs in people with cancer, but statements included in the warnings and precautions section of the label apply to all patients who are treated with ESAs.
Amgen issued a statement that it supports the changes and is in discussion with the FDA on what additional postmarketing studies are needed.
The FDA statement and additional information are available at http://www.fda.gov/Drugs/DrugSafety/ucm259639.htm. Adverse events associated with ESAs should be reported to the FDA’s MedWatch program at 800-332-1088 or http://www.fda.gov/medwatch/.
The Food and Drug Administration on June 24 issued more conservative dosing guidelines for the use of erythropoiesis-stimulating agents to treat anemia in chronic kidney disease patients who face increased risks of cardiovascular events associated with these drugs.
The new recommendations do away with a targeted range of 10-12 g/dL in hemoglobin levels in patients with chronic kidney disease (CKD). Instead, they set ceilings of 10 to 11 g/dL, depending on whether or not the anemic patient is on dialysis.
Clinicians should "individualize dosing and use the lowest dose of ESA [erythropoiesis-stimulating agent] sufficient to reduce the need for red blood cell transfusions," the agency said. The label recommends that dosing be adjusted "as appropriate."
Based on dialysis status, the new recommendations are as follows:
• If the patient is not on dialysis, the FDA advises that clinicians "consider" starting treatment with an ESA when a patient’s hemoglobin level drops below 10 g/dL "and when certain other considerations apply," for instance, if the rate of hemoglobin decline indicates that a transfusion will likely be needed.
The recommendation "does not define how far below 10 g/dL is appropriate for an individual to initiate," the agency said. It calls on clinicians to "reduce or interrupt the dose of ESA" if the patient’s level goes above 10 g/dL.
• If the patient is on dialysis, the FDA says to start ESA treatment when the patient’s hemoglobin level goes below 10 g/dL. In this case, the threshold for reducing or interrupting the ESA dose is when the hemoglobin level "approaches or exceeds 11 g/dL."
Previously, the recommendation was to dose ESAs to achieve and maintain hemoglobin levels in the target range of 10-12 g/dL; this has been removed from ESA labels. Targeting the hemoglobin level to above 11 g/dL has been found to increase the risk of myocardial infarction, stroke, and other serious adverse cardiovascular events in patients with CKD, and "has not been shown to provide additional patient benefit," the FDA statement said.
ESAs currently available in the United States are epoetin alfa (Epogen and Procrit), and darbepoetin alfa (Aranesp). All are manufactured by Amgen; Procrit is marketed by Centecor Ortho Biotech. These agents also are approved to treat anemia associated with cancer chemotherapy.
The intention of the new dosing guidelines and revised label is to "encourage flexibility" of dosing and to reinforce the message that "serious risks have been demonstrated" when the target is above 11 g/dL, Dr. Robert Kane, acting deputy director for safety in the Division of Hematology Products, FDA Center for Drug Evaluation and Research (CDER), said during a briefing.
He pointed out that the recommendations are different for patients with CKD who are on dialysis and those not on dialysis, because the risk-benefit profile is different for these groups.
The risks of ESAs in patients with CKD have been discussed at two FDA advisory panel meetings, most recently in October 2010, when an expert panel reviewed the results of the TREAT (Trial to Reduce Cardiovascular Events with Aranesp Therapy) study of darbepoetin alfa, which found an increased risk for stroke associated with a hemoglobin target of 13.0 g/dL in CKD patients not on dialysis. The new dosing recommendations have been added to the boxed warning and other sections of the label for ESAs.
Dr. Richard Pazdur, director of the FDA’s Office of Oncology Drug Products in CDER, said that the new dosing recommendations do not directly affect the use of ESAs in people with cancer, but statements included in the warnings and precautions section of the label apply to all patients who are treated with ESAs.
Amgen issued a statement that it supports the changes and is in discussion with the FDA on what additional postmarketing studies are needed.
The FDA statement and additional information are available at http://www.fda.gov/Drugs/DrugSafety/ucm259639.htm. Adverse events associated with ESAs should be reported to the FDA’s MedWatch program at 800-332-1088 or http://www.fda.gov/medwatch/.
The Food and Drug Administration on June 24 issued more conservative dosing guidelines for the use of erythropoiesis-stimulating agents to treat anemia in chronic kidney disease patients who face increased risks of cardiovascular events associated with these drugs.
The new recommendations do away with a targeted range of 10-12 g/dL in hemoglobin levels in patients with chronic kidney disease (CKD). Instead, they set ceilings of 10 to 11 g/dL, depending on whether or not the anemic patient is on dialysis.
Clinicians should "individualize dosing and use the lowest dose of ESA [erythropoiesis-stimulating agent] sufficient to reduce the need for red blood cell transfusions," the agency said. The label recommends that dosing be adjusted "as appropriate."
Based on dialysis status, the new recommendations are as follows:
• If the patient is not on dialysis, the FDA advises that clinicians "consider" starting treatment with an ESA when a patient’s hemoglobin level drops below 10 g/dL "and when certain other considerations apply," for instance, if the rate of hemoglobin decline indicates that a transfusion will likely be needed.
The recommendation "does not define how far below 10 g/dL is appropriate for an individual to initiate," the agency said. It calls on clinicians to "reduce or interrupt the dose of ESA" if the patient’s level goes above 10 g/dL.
• If the patient is on dialysis, the FDA says to start ESA treatment when the patient’s hemoglobin level goes below 10 g/dL. In this case, the threshold for reducing or interrupting the ESA dose is when the hemoglobin level "approaches or exceeds 11 g/dL."
Previously, the recommendation was to dose ESAs to achieve and maintain hemoglobin levels in the target range of 10-12 g/dL; this has been removed from ESA labels. Targeting the hemoglobin level to above 11 g/dL has been found to increase the risk of myocardial infarction, stroke, and other serious adverse cardiovascular events in patients with CKD, and "has not been shown to provide additional patient benefit," the FDA statement said.
ESAs currently available in the United States are epoetin alfa (Epogen and Procrit), and darbepoetin alfa (Aranesp). All are manufactured by Amgen; Procrit is marketed by Centecor Ortho Biotech. These agents also are approved to treat anemia associated with cancer chemotherapy.
The intention of the new dosing guidelines and revised label is to "encourage flexibility" of dosing and to reinforce the message that "serious risks have been demonstrated" when the target is above 11 g/dL, Dr. Robert Kane, acting deputy director for safety in the Division of Hematology Products, FDA Center for Drug Evaluation and Research (CDER), said during a briefing.
He pointed out that the recommendations are different for patients with CKD who are on dialysis and those not on dialysis, because the risk-benefit profile is different for these groups.
The risks of ESAs in patients with CKD have been discussed at two FDA advisory panel meetings, most recently in October 2010, when an expert panel reviewed the results of the TREAT (Trial to Reduce Cardiovascular Events with Aranesp Therapy) study of darbepoetin alfa, which found an increased risk for stroke associated with a hemoglobin target of 13.0 g/dL in CKD patients not on dialysis. The new dosing recommendations have been added to the boxed warning and other sections of the label for ESAs.
Dr. Richard Pazdur, director of the FDA’s Office of Oncology Drug Products in CDER, said that the new dosing recommendations do not directly affect the use of ESAs in people with cancer, but statements included in the warnings and precautions section of the label apply to all patients who are treated with ESAs.
Amgen issued a statement that it supports the changes and is in discussion with the FDA on what additional postmarketing studies are needed.
The FDA statement and additional information are available at http://www.fda.gov/Drugs/DrugSafety/ucm259639.htm. Adverse events associated with ESAs should be reported to the FDA’s MedWatch program at 800-332-1088 or http://www.fda.gov/medwatch/.
FROM THE FOOD AND DRUG ADMINISTRATION
Managing Recurrent UTIs in the Patient With Neurogenic Bladder
WASHINGTON – How should one manage a 35-year-old woman with multiple sclerosis on self-clean intermittent catheterization who complains of pelvic pain and cloudy urine?
Such a patient with "neurogenic bladder" and possible urinary tract infection needs careful diagnosis, catheterization review, and possibly other management considerations, said Dr. Stephen R. Kraus during a panel discussion of recurrent UTIs at the annual meeting of the American Urological Association.
Patients with neurogenic bladder commonly have chronic bacteriuria and recurrent UTIs, and thus generally require a combination of bacteriuria and leukocyturia – as well as clinical symptoms or an increase in autonomic dysreflexia – for the initiation of empirical UTI therapy. Such criteria will help avoid unnecessary use of antibiotics.
"Original criteria were based on bacterial colonization counts but were criticized for being highly insensitive," said Dr. Kraus, professor and vice chairman of the department of urology at the University of Texas, San Antonio.
Assuming the patient has already had a video urodynamic test, Dr. Kraus said, he would obtain a catheterized specimen for urinalysis, culture, and a sensitivity test; treat as needed; and then consider increasing her catheterization frequency. A trial of a hydrophilic catheter could also be considered in the context of recurrent UTIs, he said.
Various catheter modifications – from silver alloy catheters to antibiotic-impregnated catheters – have been used with some success in reducing the risk of UTIs, but "they carry their own problems such as cost, development of resistance, and even, as one study suggested, the possibility of silver toxicity," Dr. Kraus said.
Two randomized, controlled trials have shown that hydrophilic catheters will reduce the risk of UTIs, compared with regular polyvinyl chloride catheters, he noted. Although the choice of single-use vs. reusable catheters is "always a point of contention," several studies have "clearly" shown that clean intermittent catheterization (CIC) poses no greater risk of recurrent UTIs than do single-use catheters, he added.
Frequent changing of intermittent catheters can prevent biofilm development, and one study showed that UTI was five times less likely when CIC was performed six times per day rather than three times per day, he noted.
Routine chronic antibiotic prophylaxis should be avoided in patients with neurogenic bladder, he said, but a short course of antibiotics could be useful during the initial CIC period, and is certainly prudent before any invasive genitourinary procedures are performed.
Dr. Kraus said he is intrigued by the concept of a weekly oral cyclic antibiotic (WOCA) program that uses weekly alternating antibiotics as a prophylactic measure. In one 2-year trial of WOCA, investigators "saw dramatic reductions in UTIs (from 9.4 to 1.8 per patient year) ... and most importantly, they did not see any change in the number of multidrug-resistant infections," he said.
As a final management option for the above-described patient, Dr. Kraus said he would consider injections of botulinum toxin (Botox). This approach "has exploded in the market for neurogenic bladder management, and it has been associated with a significant reduction in UTI at 6 months ... presumably because the neurogenic bladder management is that much better," he said.
The term "neurogenic bladder," Dr. Kraus noted, is one that’s "not very precise." For the purposes of his discussion, he defined it as a condition in which the bladder is affected by a neurologic process and has an impaired ability to store and empty urine.
Dr. Kraus disclosed that he is an investigator for the National Institute of Diabetes and Digestive and Kidney Diseases, a course director for Laborie (which manufactures catheters and other products for urinary and pelvic disorders), and a consultant/adviser for Pfizer.
WASHINGTON – How should one manage a 35-year-old woman with multiple sclerosis on self-clean intermittent catheterization who complains of pelvic pain and cloudy urine?
Such a patient with "neurogenic bladder" and possible urinary tract infection needs careful diagnosis, catheterization review, and possibly other management considerations, said Dr. Stephen R. Kraus during a panel discussion of recurrent UTIs at the annual meeting of the American Urological Association.
Patients with neurogenic bladder commonly have chronic bacteriuria and recurrent UTIs, and thus generally require a combination of bacteriuria and leukocyturia – as well as clinical symptoms or an increase in autonomic dysreflexia – for the initiation of empirical UTI therapy. Such criteria will help avoid unnecessary use of antibiotics.
"Original criteria were based on bacterial colonization counts but were criticized for being highly insensitive," said Dr. Kraus, professor and vice chairman of the department of urology at the University of Texas, San Antonio.
Assuming the patient has already had a video urodynamic test, Dr. Kraus said, he would obtain a catheterized specimen for urinalysis, culture, and a sensitivity test; treat as needed; and then consider increasing her catheterization frequency. A trial of a hydrophilic catheter could also be considered in the context of recurrent UTIs, he said.
Various catheter modifications – from silver alloy catheters to antibiotic-impregnated catheters – have been used with some success in reducing the risk of UTIs, but "they carry their own problems such as cost, development of resistance, and even, as one study suggested, the possibility of silver toxicity," Dr. Kraus said.
Two randomized, controlled trials have shown that hydrophilic catheters will reduce the risk of UTIs, compared with regular polyvinyl chloride catheters, he noted. Although the choice of single-use vs. reusable catheters is "always a point of contention," several studies have "clearly" shown that clean intermittent catheterization (CIC) poses no greater risk of recurrent UTIs than do single-use catheters, he added.
Frequent changing of intermittent catheters can prevent biofilm development, and one study showed that UTI was five times less likely when CIC was performed six times per day rather than three times per day, he noted.
Routine chronic antibiotic prophylaxis should be avoided in patients with neurogenic bladder, he said, but a short course of antibiotics could be useful during the initial CIC period, and is certainly prudent before any invasive genitourinary procedures are performed.
Dr. Kraus said he is intrigued by the concept of a weekly oral cyclic antibiotic (WOCA) program that uses weekly alternating antibiotics as a prophylactic measure. In one 2-year trial of WOCA, investigators "saw dramatic reductions in UTIs (from 9.4 to 1.8 per patient year) ... and most importantly, they did not see any change in the number of multidrug-resistant infections," he said.
As a final management option for the above-described patient, Dr. Kraus said he would consider injections of botulinum toxin (Botox). This approach "has exploded in the market for neurogenic bladder management, and it has been associated with a significant reduction in UTI at 6 months ... presumably because the neurogenic bladder management is that much better," he said.
The term "neurogenic bladder," Dr. Kraus noted, is one that’s "not very precise." For the purposes of his discussion, he defined it as a condition in which the bladder is affected by a neurologic process and has an impaired ability to store and empty urine.
Dr. Kraus disclosed that he is an investigator for the National Institute of Diabetes and Digestive and Kidney Diseases, a course director for Laborie (which manufactures catheters and other products for urinary and pelvic disorders), and a consultant/adviser for Pfizer.
WASHINGTON – How should one manage a 35-year-old woman with multiple sclerosis on self-clean intermittent catheterization who complains of pelvic pain and cloudy urine?
Such a patient with "neurogenic bladder" and possible urinary tract infection needs careful diagnosis, catheterization review, and possibly other management considerations, said Dr. Stephen R. Kraus during a panel discussion of recurrent UTIs at the annual meeting of the American Urological Association.
Patients with neurogenic bladder commonly have chronic bacteriuria and recurrent UTIs, and thus generally require a combination of bacteriuria and leukocyturia – as well as clinical symptoms or an increase in autonomic dysreflexia – for the initiation of empirical UTI therapy. Such criteria will help avoid unnecessary use of antibiotics.
"Original criteria were based on bacterial colonization counts but were criticized for being highly insensitive," said Dr. Kraus, professor and vice chairman of the department of urology at the University of Texas, San Antonio.
Assuming the patient has already had a video urodynamic test, Dr. Kraus said, he would obtain a catheterized specimen for urinalysis, culture, and a sensitivity test; treat as needed; and then consider increasing her catheterization frequency. A trial of a hydrophilic catheter could also be considered in the context of recurrent UTIs, he said.
Various catheter modifications – from silver alloy catheters to antibiotic-impregnated catheters – have been used with some success in reducing the risk of UTIs, but "they carry their own problems such as cost, development of resistance, and even, as one study suggested, the possibility of silver toxicity," Dr. Kraus said.
Two randomized, controlled trials have shown that hydrophilic catheters will reduce the risk of UTIs, compared with regular polyvinyl chloride catheters, he noted. Although the choice of single-use vs. reusable catheters is "always a point of contention," several studies have "clearly" shown that clean intermittent catheterization (CIC) poses no greater risk of recurrent UTIs than do single-use catheters, he added.
Frequent changing of intermittent catheters can prevent biofilm development, and one study showed that UTI was five times less likely when CIC was performed six times per day rather than three times per day, he noted.
Routine chronic antibiotic prophylaxis should be avoided in patients with neurogenic bladder, he said, but a short course of antibiotics could be useful during the initial CIC period, and is certainly prudent before any invasive genitourinary procedures are performed.
Dr. Kraus said he is intrigued by the concept of a weekly oral cyclic antibiotic (WOCA) program that uses weekly alternating antibiotics as a prophylactic measure. In one 2-year trial of WOCA, investigators "saw dramatic reductions in UTIs (from 9.4 to 1.8 per patient year) ... and most importantly, they did not see any change in the number of multidrug-resistant infections," he said.
As a final management option for the above-described patient, Dr. Kraus said he would consider injections of botulinum toxin (Botox). This approach "has exploded in the market for neurogenic bladder management, and it has been associated with a significant reduction in UTI at 6 months ... presumably because the neurogenic bladder management is that much better," he said.
The term "neurogenic bladder," Dr. Kraus noted, is one that’s "not very precise." For the purposes of his discussion, he defined it as a condition in which the bladder is affected by a neurologic process and has an impaired ability to store and empty urine.
Dr. Kraus disclosed that he is an investigator for the National Institute of Diabetes and Digestive and Kidney Diseases, a course director for Laborie (which manufactures catheters and other products for urinary and pelvic disorders), and a consultant/adviser for Pfizer.
EXPERT ANALYSIS FROM THE ANNUAL MEETING OF THE AMERICAN UROLOGICAL ASSOCIATION
Managing Recurrent UTIs in the Patient With Neurogenic Bladder
WASHINGTON – How should one manage a 35-year-old woman with multiple sclerosis on self-clean intermittent catheterization who complains of pelvic pain and cloudy urine?
Such a patient with "neurogenic bladder" and possible urinary tract infection needs careful diagnosis, catheterization review, and possibly other management considerations, said Dr. Stephen R. Kraus during a panel discussion of recurrent UTIs at the annual meeting of the American Urological Association.
Patients with neurogenic bladder commonly have chronic bacteriuria and recurrent UTIs, and thus generally require a combination of bacteriuria and leukocyturia – as well as clinical symptoms or an increase in autonomic dysreflexia – for the initiation of empirical UTI therapy. Such criteria will help avoid unnecessary use of antibiotics.
"Original criteria were based on bacterial colonization counts but were criticized for being highly insensitive," said Dr. Kraus, professor and vice chairman of the department of urology at the University of Texas, San Antonio.
Assuming the patient has already had a video urodynamic test, Dr. Kraus said, he would obtain a catheterized specimen for urinalysis, culture, and a sensitivity test; treat as needed; and then consider increasing her catheterization frequency. A trial of a hydrophilic catheter could also be considered in the context of recurrent UTIs, he said.
Various catheter modifications – from silver alloy catheters to antibiotic-impregnated catheters – have been used with some success in reducing the risk of UTIs, but "they carry their own problems such as cost, development of resistance, and even, as one study suggested, the possibility of silver toxicity," Dr. Kraus said.
Two randomized, controlled trials have shown that hydrophilic catheters will reduce the risk of UTIs, compared with regular polyvinyl chloride catheters, he noted. Although the choice of single-use vs. reusable catheters is "always a point of contention," several studies have "clearly" shown that clean intermittent catheterization (CIC) poses no greater risk of recurrent UTIs than do single-use catheters, he added.
Frequent changing of intermittent catheters can prevent biofilm development, and one study showed that UTI was five times less likely when CIC was performed six times per day rather than three times per day, he noted.
Routine chronic antibiotic prophylaxis should be avoided in patients with neurogenic bladder, he said, but a short course of antibiotics could be useful during the initial CIC period, and is certainly prudent before any invasive genitourinary procedures are performed.
Dr. Kraus said he is intrigued by the concept of a weekly oral cyclic antibiotic (WOCA) program that uses weekly alternating antibiotics as a prophylactic measure. In one 2-year trial of WOCA, investigators "saw dramatic reductions in UTIs (from 9.4 to 1.8 per patient year) ... and most importantly, they did not see any change in the number of multidrug-resistant infections," he said.
As a final management option for the above-described patient, Dr. Kraus said he would consider injections of botulinum toxin (Botox). This approach "has exploded in the market for neurogenic bladder management, and it has been associated with a significant reduction in UTI at 6 months ... presumably because the neurogenic bladder management is that much better," he said.
The term "neurogenic bladder," Dr. Kraus noted, is one that’s "not very precise." For the purposes of his discussion, he defined it as a condition in which the bladder is affected by a neurologic process and has an impaired ability to store and empty urine.
Dr. Kraus disclosed that he is an investigator for the National Institute of Diabetes and Digestive and Kidney Diseases, a course director for Laborie (which manufactures catheters and other products for urinary and pelvic disorders), and a consultant/adviser for Pfizer.
WASHINGTON – How should one manage a 35-year-old woman with multiple sclerosis on self-clean intermittent catheterization who complains of pelvic pain and cloudy urine?
Such a patient with "neurogenic bladder" and possible urinary tract infection needs careful diagnosis, catheterization review, and possibly other management considerations, said Dr. Stephen R. Kraus during a panel discussion of recurrent UTIs at the annual meeting of the American Urological Association.
Patients with neurogenic bladder commonly have chronic bacteriuria and recurrent UTIs, and thus generally require a combination of bacteriuria and leukocyturia – as well as clinical symptoms or an increase in autonomic dysreflexia – for the initiation of empirical UTI therapy. Such criteria will help avoid unnecessary use of antibiotics.
"Original criteria were based on bacterial colonization counts but were criticized for being highly insensitive," said Dr. Kraus, professor and vice chairman of the department of urology at the University of Texas, San Antonio.
Assuming the patient has already had a video urodynamic test, Dr. Kraus said, he would obtain a catheterized specimen for urinalysis, culture, and a sensitivity test; treat as needed; and then consider increasing her catheterization frequency. A trial of a hydrophilic catheter could also be considered in the context of recurrent UTIs, he said.
Various catheter modifications – from silver alloy catheters to antibiotic-impregnated catheters – have been used with some success in reducing the risk of UTIs, but "they carry their own problems such as cost, development of resistance, and even, as one study suggested, the possibility of silver toxicity," Dr. Kraus said.
Two randomized, controlled trials have shown that hydrophilic catheters will reduce the risk of UTIs, compared with regular polyvinyl chloride catheters, he noted. Although the choice of single-use vs. reusable catheters is "always a point of contention," several studies have "clearly" shown that clean intermittent catheterization (CIC) poses no greater risk of recurrent UTIs than do single-use catheters, he added.
Frequent changing of intermittent catheters can prevent biofilm development, and one study showed that UTI was five times less likely when CIC was performed six times per day rather than three times per day, he noted.
Routine chronic antibiotic prophylaxis should be avoided in patients with neurogenic bladder, he said, but a short course of antibiotics could be useful during the initial CIC period, and is certainly prudent before any invasive genitourinary procedures are performed.
Dr. Kraus said he is intrigued by the concept of a weekly oral cyclic antibiotic (WOCA) program that uses weekly alternating antibiotics as a prophylactic measure. In one 2-year trial of WOCA, investigators "saw dramatic reductions in UTIs (from 9.4 to 1.8 per patient year) ... and most importantly, they did not see any change in the number of multidrug-resistant infections," he said.
As a final management option for the above-described patient, Dr. Kraus said he would consider injections of botulinum toxin (Botox). This approach "has exploded in the market for neurogenic bladder management, and it has been associated with a significant reduction in UTI at 6 months ... presumably because the neurogenic bladder management is that much better," he said.
The term "neurogenic bladder," Dr. Kraus noted, is one that’s "not very precise." For the purposes of his discussion, he defined it as a condition in which the bladder is affected by a neurologic process and has an impaired ability to store and empty urine.
Dr. Kraus disclosed that he is an investigator for the National Institute of Diabetes and Digestive and Kidney Diseases, a course director for Laborie (which manufactures catheters and other products for urinary and pelvic disorders), and a consultant/adviser for Pfizer.
WASHINGTON – How should one manage a 35-year-old woman with multiple sclerosis on self-clean intermittent catheterization who complains of pelvic pain and cloudy urine?
Such a patient with "neurogenic bladder" and possible urinary tract infection needs careful diagnosis, catheterization review, and possibly other management considerations, said Dr. Stephen R. Kraus during a panel discussion of recurrent UTIs at the annual meeting of the American Urological Association.
Patients with neurogenic bladder commonly have chronic bacteriuria and recurrent UTIs, and thus generally require a combination of bacteriuria and leukocyturia – as well as clinical symptoms or an increase in autonomic dysreflexia – for the initiation of empirical UTI therapy. Such criteria will help avoid unnecessary use of antibiotics.
"Original criteria were based on bacterial colonization counts but were criticized for being highly insensitive," said Dr. Kraus, professor and vice chairman of the department of urology at the University of Texas, San Antonio.
Assuming the patient has already had a video urodynamic test, Dr. Kraus said, he would obtain a catheterized specimen for urinalysis, culture, and a sensitivity test; treat as needed; and then consider increasing her catheterization frequency. A trial of a hydrophilic catheter could also be considered in the context of recurrent UTIs, he said.
Various catheter modifications – from silver alloy catheters to antibiotic-impregnated catheters – have been used with some success in reducing the risk of UTIs, but "they carry their own problems such as cost, development of resistance, and even, as one study suggested, the possibility of silver toxicity," Dr. Kraus said.
Two randomized, controlled trials have shown that hydrophilic catheters will reduce the risk of UTIs, compared with regular polyvinyl chloride catheters, he noted. Although the choice of single-use vs. reusable catheters is "always a point of contention," several studies have "clearly" shown that clean intermittent catheterization (CIC) poses no greater risk of recurrent UTIs than do single-use catheters, he added.
Frequent changing of intermittent catheters can prevent biofilm development, and one study showed that UTI was five times less likely when CIC was performed six times per day rather than three times per day, he noted.
Routine chronic antibiotic prophylaxis should be avoided in patients with neurogenic bladder, he said, but a short course of antibiotics could be useful during the initial CIC period, and is certainly prudent before any invasive genitourinary procedures are performed.
Dr. Kraus said he is intrigued by the concept of a weekly oral cyclic antibiotic (WOCA) program that uses weekly alternating antibiotics as a prophylactic measure. In one 2-year trial of WOCA, investigators "saw dramatic reductions in UTIs (from 9.4 to 1.8 per patient year) ... and most importantly, they did not see any change in the number of multidrug-resistant infections," he said.
As a final management option for the above-described patient, Dr. Kraus said he would consider injections of botulinum toxin (Botox). This approach "has exploded in the market for neurogenic bladder management, and it has been associated with a significant reduction in UTI at 6 months ... presumably because the neurogenic bladder management is that much better," he said.
The term "neurogenic bladder," Dr. Kraus noted, is one that’s "not very precise." For the purposes of his discussion, he defined it as a condition in which the bladder is affected by a neurologic process and has an impaired ability to store and empty urine.
Dr. Kraus disclosed that he is an investigator for the National Institute of Diabetes and Digestive and Kidney Diseases, a course director for Laborie (which manufactures catheters and other products for urinary and pelvic disorders), and a consultant/adviser for Pfizer.
EXPERT ANALYSIS FROM THE ANNUAL MEETING OF THE AMERICAN UROLOGICAL ASSOCIATION
Rapid Molecular Diagnosis Deemed a Game Changer for UTI Management
WASHINGTON – Rapid molecular diagnosis of urinary tract infection will soon enable individualized, evidence-based selection of antibiotics "right at the point of care," according to Dr. Joseph C. Liao.
"Currently we rely on urine culture, which takes 2-3 days at a central microbiology laboratory," he said. "What if in the future [you] could obtain molecular diagnosis in less than 1 hour right there in your office? And what if we could tailor the choice of antibiotics for the patient sitting in your office [rather than start broad-spectrum antibiotics empirically]?"
Personalized, evidence-based selection of antibiotics has become an increasingly important goal – for both individual and public health – as the problem of antibiotic resistance has intensified, said Dr. Liao and other speakers at the annual meeting of the American Urological Association.
Over the past several years, Dr. Liao and his colleagues in the urology department at Stanford (Calif.) University have used biosensor technology to develop an assay for rapid pathogen identification, as well as a biosensor-based antimicrobial susceptibility test for urinary tract infection (UTI).
"We’ve been able to achieve pathogen identification within an hour, and antimicrobial susceptibility testing within 3 hours," Dr. Liao reported.
The biosensor (a molecular sensing device that generates a measurable signal in the presence of a target analyte) is already part of everyday clinical practice, he noted. The glucose sensor and the i-STAT portable clinical analyzer, for example, are commonly used biosensor-based devices.
The biosensor being utilized in the "next generation" of UTI diagnostic tools is comprised of a chip about the size of a microscope slide with 16 individual sensors. "Like computer technology, it can be mass produced at a relatively low cost," said Dr. Liao, who is also chief urologist at the Veterans Affairs Palo Alto (Calif.) Health Care System.
The overall strategy for pathogen identification involves lysis of the bacteria present in a urine sample, followed by a hybridization process that enables the sensor to detect bacterial 16S rRNA, a kind of "bacterial molecular fingerprint." This results in a signal output.
"Essentially, we’re converting a molecular hybridization event into an electrical signal," Dr. Liao explained. "And the higher the bacterial concentration, the higher the signal."
Bacterial 16S rRNA is also a marker of bacterial growth, a property that Dr. Liao’s research group has exploited to develop a biosensor-based antimicrobial susceptibility test (AST). By incubating a urine sample in the presence or absence of commonly used antibiotics, and quantifying the 16S rRNA level, "we can follow the differential growth and derive the AST," he said.
Dr. Liao and his colleagues recently completed a clinical validation study in which they compared results from their biosensor platform with results from standard microbiological analysis in more than 200 urine samples collected from patients at the Spinal Cord Injury Service at the Veterans Affairs Palo Alto system.
Pathogen detection sensitivity and specificity were 92% and 97%, respectively, and "in corresponding AST, we found an overall agreement of 94%," said Dr. Liao, whose study was published early this year (J. Urol. 2011;185:148-53).
In the future, Dr. Liao hopes to use biosensor technology to also detect biomarkers that are shown to be indicative of infection in the presence of pathogens, he said. Such an integrated assay would detect both biomarkers and pathogens, and thus address the host immunity response as well as identify the pathogen. This could further improve the now-challenging task of differentiating colonization, simple UTI, and early complicated UTI, "and [could] help us better differentiate and stratify the severity of infection," he said.
Dr. Liao reported that he had no disclosures.
WASHINGTON – Rapid molecular diagnosis of urinary tract infection will soon enable individualized, evidence-based selection of antibiotics "right at the point of care," according to Dr. Joseph C. Liao.
"Currently we rely on urine culture, which takes 2-3 days at a central microbiology laboratory," he said. "What if in the future [you] could obtain molecular diagnosis in less than 1 hour right there in your office? And what if we could tailor the choice of antibiotics for the patient sitting in your office [rather than start broad-spectrum antibiotics empirically]?"
Personalized, evidence-based selection of antibiotics has become an increasingly important goal – for both individual and public health – as the problem of antibiotic resistance has intensified, said Dr. Liao and other speakers at the annual meeting of the American Urological Association.
Over the past several years, Dr. Liao and his colleagues in the urology department at Stanford (Calif.) University have used biosensor technology to develop an assay for rapid pathogen identification, as well as a biosensor-based antimicrobial susceptibility test for urinary tract infection (UTI).
"We’ve been able to achieve pathogen identification within an hour, and antimicrobial susceptibility testing within 3 hours," Dr. Liao reported.
The biosensor (a molecular sensing device that generates a measurable signal in the presence of a target analyte) is already part of everyday clinical practice, he noted. The glucose sensor and the i-STAT portable clinical analyzer, for example, are commonly used biosensor-based devices.
The biosensor being utilized in the "next generation" of UTI diagnostic tools is comprised of a chip about the size of a microscope slide with 16 individual sensors. "Like computer technology, it can be mass produced at a relatively low cost," said Dr. Liao, who is also chief urologist at the Veterans Affairs Palo Alto (Calif.) Health Care System.
The overall strategy for pathogen identification involves lysis of the bacteria present in a urine sample, followed by a hybridization process that enables the sensor to detect bacterial 16S rRNA, a kind of "bacterial molecular fingerprint." This results in a signal output.
"Essentially, we’re converting a molecular hybridization event into an electrical signal," Dr. Liao explained. "And the higher the bacterial concentration, the higher the signal."
Bacterial 16S rRNA is also a marker of bacterial growth, a property that Dr. Liao’s research group has exploited to develop a biosensor-based antimicrobial susceptibility test (AST). By incubating a urine sample in the presence or absence of commonly used antibiotics, and quantifying the 16S rRNA level, "we can follow the differential growth and derive the AST," he said.
Dr. Liao and his colleagues recently completed a clinical validation study in which they compared results from their biosensor platform with results from standard microbiological analysis in more than 200 urine samples collected from patients at the Spinal Cord Injury Service at the Veterans Affairs Palo Alto system.
Pathogen detection sensitivity and specificity were 92% and 97%, respectively, and "in corresponding AST, we found an overall agreement of 94%," said Dr. Liao, whose study was published early this year (J. Urol. 2011;185:148-53).
In the future, Dr. Liao hopes to use biosensor technology to also detect biomarkers that are shown to be indicative of infection in the presence of pathogens, he said. Such an integrated assay would detect both biomarkers and pathogens, and thus address the host immunity response as well as identify the pathogen. This could further improve the now-challenging task of differentiating colonization, simple UTI, and early complicated UTI, "and [could] help us better differentiate and stratify the severity of infection," he said.
Dr. Liao reported that he had no disclosures.
WASHINGTON – Rapid molecular diagnosis of urinary tract infection will soon enable individualized, evidence-based selection of antibiotics "right at the point of care," according to Dr. Joseph C. Liao.
"Currently we rely on urine culture, which takes 2-3 days at a central microbiology laboratory," he said. "What if in the future [you] could obtain molecular diagnosis in less than 1 hour right there in your office? And what if we could tailor the choice of antibiotics for the patient sitting in your office [rather than start broad-spectrum antibiotics empirically]?"
Personalized, evidence-based selection of antibiotics has become an increasingly important goal – for both individual and public health – as the problem of antibiotic resistance has intensified, said Dr. Liao and other speakers at the annual meeting of the American Urological Association.
Over the past several years, Dr. Liao and his colleagues in the urology department at Stanford (Calif.) University have used biosensor technology to develop an assay for rapid pathogen identification, as well as a biosensor-based antimicrobial susceptibility test for urinary tract infection (UTI).
"We’ve been able to achieve pathogen identification within an hour, and antimicrobial susceptibility testing within 3 hours," Dr. Liao reported.
The biosensor (a molecular sensing device that generates a measurable signal in the presence of a target analyte) is already part of everyday clinical practice, he noted. The glucose sensor and the i-STAT portable clinical analyzer, for example, are commonly used biosensor-based devices.
The biosensor being utilized in the "next generation" of UTI diagnostic tools is comprised of a chip about the size of a microscope slide with 16 individual sensors. "Like computer technology, it can be mass produced at a relatively low cost," said Dr. Liao, who is also chief urologist at the Veterans Affairs Palo Alto (Calif.) Health Care System.
The overall strategy for pathogen identification involves lysis of the bacteria present in a urine sample, followed by a hybridization process that enables the sensor to detect bacterial 16S rRNA, a kind of "bacterial molecular fingerprint." This results in a signal output.
"Essentially, we’re converting a molecular hybridization event into an electrical signal," Dr. Liao explained. "And the higher the bacterial concentration, the higher the signal."
Bacterial 16S rRNA is also a marker of bacterial growth, a property that Dr. Liao’s research group has exploited to develop a biosensor-based antimicrobial susceptibility test (AST). By incubating a urine sample in the presence or absence of commonly used antibiotics, and quantifying the 16S rRNA level, "we can follow the differential growth and derive the AST," he said.
Dr. Liao and his colleagues recently completed a clinical validation study in which they compared results from their biosensor platform with results from standard microbiological analysis in more than 200 urine samples collected from patients at the Spinal Cord Injury Service at the Veterans Affairs Palo Alto system.
Pathogen detection sensitivity and specificity were 92% and 97%, respectively, and "in corresponding AST, we found an overall agreement of 94%," said Dr. Liao, whose study was published early this year (J. Urol. 2011;185:148-53).
In the future, Dr. Liao hopes to use biosensor technology to also detect biomarkers that are shown to be indicative of infection in the presence of pathogens, he said. Such an integrated assay would detect both biomarkers and pathogens, and thus address the host immunity response as well as identify the pathogen. This could further improve the now-challenging task of differentiating colonization, simple UTI, and early complicated UTI, "and [could] help us better differentiate and stratify the severity of infection," he said.
Dr. Liao reported that he had no disclosures.
EXPERT ANALYSIS FROM THE ANNUAL MEETING OF THE AMERICAN UROLGICAL ASSOCIATION
KEEP Results Show Promise of New Equation
NEW YORK – Boosting patient awareness and use of a new equation for measuring glomerular filtration rate are showing early signs of being the cornerstones to the prevention of chronic kidney disease among people at risk for the disease, according to preliminary results from the National Kidney Foundation’s nationwide screening initiative.
The Kidney Early Evaluation Program (KEEP) has enrolled 150,000 people so far, making it the nation’s largest perpetual chronic kidney disease screening program, according to Dr. Joseph Vassalotti, chief medical officer of the National Kidney Foundation and a faculty member at Mount Sinai School of Medicine, New York.
The point is to identify "individuals in the community with kidney disease along with the risk factors that go with it," said Dr. George Bakris of the University of Chicago Medical Center and a former KEEP principal investigator. All of the participants have some stage of kidney disease or hypertension and are referred to the registry by physicians. Enrollment is voluntary and participants complete a questionnaire and undergo a medical evaluation that includes standard panels plus testing for calcium, phosphorus, and parathyroid hormone. The program does not accept people who have had a kidney transplant or are on dialysis, he said.
Under the program, a new method for estimating glomerular filtration rate (eGFR), known as the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, has been used. This equation is more accurate in determining kidney function than is the Modification of Diet in Renal Disease (MDRD) Study equation, said Dr. Lesley Stevens of Tufts Medical Center, Boston. "The use of the CKD-EPI equation more accurately reflects measured GFR and results in a lower prevalence of eGFR below 60 mL/min per 1.73 m2," said Dr. Stevens, a KEEP committee member. As a result, there are fewer false positives and "ultimately, fewer tests and lower costs," she said.
According to Dr. Stevens, the equation has been validated in two clinical studies (Am. J. Kidney Dis. 2010;55:648-59 and Am. J. Kidney Dis. 2010;55:660-70).
One of the goals of KEEP is to determine factors that help slow the slide into chronic kidney disease, as well as the loss of kidney function over time, Dr. Vassalotti said. "Multiple trials on systolic blood pressure show that untreated hypertension results in a loss of 10-12 mL/min per 1.73 m2 eGFR a year," he said. "In individuals with blood pressure in the target range, the annual loss is approximately 2-3 mL/min per 1.73 m2. By educating participants and fostering their engagement with local clinicians, KEEP can impact care."
Managing blood pressure early in kidney disease is critical because as eGFR declines, hypertension becomes more difficult to control, Dr. Vassalotti said. Thus, self-reported hypertension is one of the qualifiers for KEEP enrollment, he said. He cited early data from KEEP that showed prevalence, awareness and treatment of hypertension increased with stage of chronic kidney disease, but that didn’t necessarily translate to control with severe disease. Among those with stage 3 disease, only 82% were undergoing treatment, compared with 92% of those with stage 4 disease. However, 38% of the stage 3 group had systolic blood pressure below 140 mm Hg, while only 35% of the stage 4 group did (Am. J. Med. 2008; 121:332-40).
KEEP data have shown an uptick in overall blood pressure control, from 45% at the initial screening to 49% at rescreening, Dr. Vassalotti said, and even some improvement in control without medication. "But I wouldn’t overstate this."
The project involves merging data with the National Death Index and the United States Renal Data System to track survival and chronic kidney failure outcomes, respectively. Future goals include additional data links with Medicare Parts B and D to gain clarity on morbidity and medication use, Dr. Vassalotti said. "Preliminary longitudinal data show that community screening appears to influence hypertension despite progression of chronic kidney disease," he said.
Patient awareness is the cornerstone of hypertension management, noted Dr. Adam Whaley-Connell of the University of Missouri. "Awareness has a very important role in not only understanding blood pressure control, especially in the context of the early stages of kidney disease, but in improving kidney related patient outcomes," he said. However, he noted that awareness of kidney disease, particularly in its early stages, "is alarmingly low."
He noted that KEEP data on awareness reflect that of National Health and Nutrition Examination Survey and other CKD cohort studies: Only about 5% of those with stages 1-3 are aware of their disease. "Roughly 95% of individuals entering into the screening program are unaware they have chronic kidney disease," Dr. Whaley-Connell said.
KEEP enrollees with cardiovascular disease had a keener awareness of the risks of kidney disease, he said. "While awareness may be triggered by cardiovascular disease, those unaware in the earlier stages of kidney disease are particularly vulnerable to poor risk factor control and increased risk for mortality and progression to end-stage renal disease," Dr. Whaley-Connell said. "We advocate for targeted education and awareness at earlier stages of kidney disease to improve risk factor control."
"I think any general practitioner seeing patients needs to pay attention to eGFR," Dr. Bakris said. "If the patient has stage 2 disease and an eGFR of 60-80 mL/min per 1.73 m2 now, especially with the CKD-EPI equation, the next question out of his mouth should be, ‘Do you have a family history of kidney disease?’"
However, he cited National Kidney Foundation data that showed only 31% of physicians considered family history an important factor. "If your patient has a family history of kidney disease and an eGFR of 50 mL/min per 1.73 m2 ... you really do need to pay attention to that and do something about it."
KEEP is funded by Amgen, Abbott, Siemens, Astellas, Genzyme, Fresenius Medical Care, Pfizer, Nephroceuticals and the LifeScan unit of Johnson & Johnson. Panel participants disclosed affiliations with a variety of device and pharmaceutical companies.
NEW YORK – Boosting patient awareness and use of a new equation for measuring glomerular filtration rate are showing early signs of being the cornerstones to the prevention of chronic kidney disease among people at risk for the disease, according to preliminary results from the National Kidney Foundation’s nationwide screening initiative.
The Kidney Early Evaluation Program (KEEP) has enrolled 150,000 people so far, making it the nation’s largest perpetual chronic kidney disease screening program, according to Dr. Joseph Vassalotti, chief medical officer of the National Kidney Foundation and a faculty member at Mount Sinai School of Medicine, New York.
The point is to identify "individuals in the community with kidney disease along with the risk factors that go with it," said Dr. George Bakris of the University of Chicago Medical Center and a former KEEP principal investigator. All of the participants have some stage of kidney disease or hypertension and are referred to the registry by physicians. Enrollment is voluntary and participants complete a questionnaire and undergo a medical evaluation that includes standard panels plus testing for calcium, phosphorus, and parathyroid hormone. The program does not accept people who have had a kidney transplant or are on dialysis, he said.
Under the program, a new method for estimating glomerular filtration rate (eGFR), known as the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, has been used. This equation is more accurate in determining kidney function than is the Modification of Diet in Renal Disease (MDRD) Study equation, said Dr. Lesley Stevens of Tufts Medical Center, Boston. "The use of the CKD-EPI equation more accurately reflects measured GFR and results in a lower prevalence of eGFR below 60 mL/min per 1.73 m2," said Dr. Stevens, a KEEP committee member. As a result, there are fewer false positives and "ultimately, fewer tests and lower costs," she said.
According to Dr. Stevens, the equation has been validated in two clinical studies (Am. J. Kidney Dis. 2010;55:648-59 and Am. J. Kidney Dis. 2010;55:660-70).
One of the goals of KEEP is to determine factors that help slow the slide into chronic kidney disease, as well as the loss of kidney function over time, Dr. Vassalotti said. "Multiple trials on systolic blood pressure show that untreated hypertension results in a loss of 10-12 mL/min per 1.73 m2 eGFR a year," he said. "In individuals with blood pressure in the target range, the annual loss is approximately 2-3 mL/min per 1.73 m2. By educating participants and fostering their engagement with local clinicians, KEEP can impact care."
Managing blood pressure early in kidney disease is critical because as eGFR declines, hypertension becomes more difficult to control, Dr. Vassalotti said. Thus, self-reported hypertension is one of the qualifiers for KEEP enrollment, he said. He cited early data from KEEP that showed prevalence, awareness and treatment of hypertension increased with stage of chronic kidney disease, but that didn’t necessarily translate to control with severe disease. Among those with stage 3 disease, only 82% were undergoing treatment, compared with 92% of those with stage 4 disease. However, 38% of the stage 3 group had systolic blood pressure below 140 mm Hg, while only 35% of the stage 4 group did (Am. J. Med. 2008; 121:332-40).
KEEP data have shown an uptick in overall blood pressure control, from 45% at the initial screening to 49% at rescreening, Dr. Vassalotti said, and even some improvement in control without medication. "But I wouldn’t overstate this."
The project involves merging data with the National Death Index and the United States Renal Data System to track survival and chronic kidney failure outcomes, respectively. Future goals include additional data links with Medicare Parts B and D to gain clarity on morbidity and medication use, Dr. Vassalotti said. "Preliminary longitudinal data show that community screening appears to influence hypertension despite progression of chronic kidney disease," he said.
Patient awareness is the cornerstone of hypertension management, noted Dr. Adam Whaley-Connell of the University of Missouri. "Awareness has a very important role in not only understanding blood pressure control, especially in the context of the early stages of kidney disease, but in improving kidney related patient outcomes," he said. However, he noted that awareness of kidney disease, particularly in its early stages, "is alarmingly low."
He noted that KEEP data on awareness reflect that of National Health and Nutrition Examination Survey and other CKD cohort studies: Only about 5% of those with stages 1-3 are aware of their disease. "Roughly 95% of individuals entering into the screening program are unaware they have chronic kidney disease," Dr. Whaley-Connell said.
KEEP enrollees with cardiovascular disease had a keener awareness of the risks of kidney disease, he said. "While awareness may be triggered by cardiovascular disease, those unaware in the earlier stages of kidney disease are particularly vulnerable to poor risk factor control and increased risk for mortality and progression to end-stage renal disease," Dr. Whaley-Connell said. "We advocate for targeted education and awareness at earlier stages of kidney disease to improve risk factor control."
"I think any general practitioner seeing patients needs to pay attention to eGFR," Dr. Bakris said. "If the patient has stage 2 disease and an eGFR of 60-80 mL/min per 1.73 m2 now, especially with the CKD-EPI equation, the next question out of his mouth should be, ‘Do you have a family history of kidney disease?’"
However, he cited National Kidney Foundation data that showed only 31% of physicians considered family history an important factor. "If your patient has a family history of kidney disease and an eGFR of 50 mL/min per 1.73 m2 ... you really do need to pay attention to that and do something about it."
KEEP is funded by Amgen, Abbott, Siemens, Astellas, Genzyme, Fresenius Medical Care, Pfizer, Nephroceuticals and the LifeScan unit of Johnson & Johnson. Panel participants disclosed affiliations with a variety of device and pharmaceutical companies.
NEW YORK – Boosting patient awareness and use of a new equation for measuring glomerular filtration rate are showing early signs of being the cornerstones to the prevention of chronic kidney disease among people at risk for the disease, according to preliminary results from the National Kidney Foundation’s nationwide screening initiative.
The Kidney Early Evaluation Program (KEEP) has enrolled 150,000 people so far, making it the nation’s largest perpetual chronic kidney disease screening program, according to Dr. Joseph Vassalotti, chief medical officer of the National Kidney Foundation and a faculty member at Mount Sinai School of Medicine, New York.
The point is to identify "individuals in the community with kidney disease along with the risk factors that go with it," said Dr. George Bakris of the University of Chicago Medical Center and a former KEEP principal investigator. All of the participants have some stage of kidney disease or hypertension and are referred to the registry by physicians. Enrollment is voluntary and participants complete a questionnaire and undergo a medical evaluation that includes standard panels plus testing for calcium, phosphorus, and parathyroid hormone. The program does not accept people who have had a kidney transplant or are on dialysis, he said.
Under the program, a new method for estimating glomerular filtration rate (eGFR), known as the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, has been used. This equation is more accurate in determining kidney function than is the Modification of Diet in Renal Disease (MDRD) Study equation, said Dr. Lesley Stevens of Tufts Medical Center, Boston. "The use of the CKD-EPI equation more accurately reflects measured GFR and results in a lower prevalence of eGFR below 60 mL/min per 1.73 m2," said Dr. Stevens, a KEEP committee member. As a result, there are fewer false positives and "ultimately, fewer tests and lower costs," she said.
According to Dr. Stevens, the equation has been validated in two clinical studies (Am. J. Kidney Dis. 2010;55:648-59 and Am. J. Kidney Dis. 2010;55:660-70).
One of the goals of KEEP is to determine factors that help slow the slide into chronic kidney disease, as well as the loss of kidney function over time, Dr. Vassalotti said. "Multiple trials on systolic blood pressure show that untreated hypertension results in a loss of 10-12 mL/min per 1.73 m2 eGFR a year," he said. "In individuals with blood pressure in the target range, the annual loss is approximately 2-3 mL/min per 1.73 m2. By educating participants and fostering their engagement with local clinicians, KEEP can impact care."
Managing blood pressure early in kidney disease is critical because as eGFR declines, hypertension becomes more difficult to control, Dr. Vassalotti said. Thus, self-reported hypertension is one of the qualifiers for KEEP enrollment, he said. He cited early data from KEEP that showed prevalence, awareness and treatment of hypertension increased with stage of chronic kidney disease, but that didn’t necessarily translate to control with severe disease. Among those with stage 3 disease, only 82% were undergoing treatment, compared with 92% of those with stage 4 disease. However, 38% of the stage 3 group had systolic blood pressure below 140 mm Hg, while only 35% of the stage 4 group did (Am. J. Med. 2008; 121:332-40).
KEEP data have shown an uptick in overall blood pressure control, from 45% at the initial screening to 49% at rescreening, Dr. Vassalotti said, and even some improvement in control without medication. "But I wouldn’t overstate this."
The project involves merging data with the National Death Index and the United States Renal Data System to track survival and chronic kidney failure outcomes, respectively. Future goals include additional data links with Medicare Parts B and D to gain clarity on morbidity and medication use, Dr. Vassalotti said. "Preliminary longitudinal data show that community screening appears to influence hypertension despite progression of chronic kidney disease," he said.
Patient awareness is the cornerstone of hypertension management, noted Dr. Adam Whaley-Connell of the University of Missouri. "Awareness has a very important role in not only understanding blood pressure control, especially in the context of the early stages of kidney disease, but in improving kidney related patient outcomes," he said. However, he noted that awareness of kidney disease, particularly in its early stages, "is alarmingly low."
He noted that KEEP data on awareness reflect that of National Health and Nutrition Examination Survey and other CKD cohort studies: Only about 5% of those with stages 1-3 are aware of their disease. "Roughly 95% of individuals entering into the screening program are unaware they have chronic kidney disease," Dr. Whaley-Connell said.
KEEP enrollees with cardiovascular disease had a keener awareness of the risks of kidney disease, he said. "While awareness may be triggered by cardiovascular disease, those unaware in the earlier stages of kidney disease are particularly vulnerable to poor risk factor control and increased risk for mortality and progression to end-stage renal disease," Dr. Whaley-Connell said. "We advocate for targeted education and awareness at earlier stages of kidney disease to improve risk factor control."
"I think any general practitioner seeing patients needs to pay attention to eGFR," Dr. Bakris said. "If the patient has stage 2 disease and an eGFR of 60-80 mL/min per 1.73 m2 now, especially with the CKD-EPI equation, the next question out of his mouth should be, ‘Do you have a family history of kidney disease?’"
However, he cited National Kidney Foundation data that showed only 31% of physicians considered family history an important factor. "If your patient has a family history of kidney disease and an eGFR of 50 mL/min per 1.73 m2 ... you really do need to pay attention to that and do something about it."
KEEP is funded by Amgen, Abbott, Siemens, Astellas, Genzyme, Fresenius Medical Care, Pfizer, Nephroceuticals and the LifeScan unit of Johnson & Johnson. Panel participants disclosed affiliations with a variety of device and pharmaceutical companies.
FROM THE ANNUAL MEETING OF THE AMERICAN SOCIETY OF HYPERTENSION
Major Finding: KEEP data have shown an uptick in overall blood pressure control among patients with early-stage kidney disease or hypertension, from 45% at the initial screening to 49% at rescreening.
Data Source: Preliminary results from the National Kidney Foundation’s screening initiative.
Disclosures: KEEP is funded by Amgen, Abbott, Siemens, Astellas, Genzyme, Fresenius Medical Care, Pfizer, Nephroceuticals and the LifeScan unit of Johnson & Johnson. Panel participants disclosed affiliations with a variety of device and pharmaceutical companies.