VOLUME 11, ISSUE NUMBER 8
Intermittent Inferior to Continuous ADT
ADT Approaches Not Equal A new study shows that continuous androgen deprivation therapy (ADT) offers better survival than intermittent ADT among men with metastatic prostate cancer.
Overall survival is worse, data show BY JOHN SCHIESZER CHICAGO—Intermittent androgen deprivation therapy (ADT) has some quality of life benefits for men with metastatic prostate cancer (PCa), but overall survival times are inferior to those seen with continuous ADT, according to the findings of a 17-year study (SWOG9346) presented at the American Society for Clinical Oncology 2012 annual meeting. “Some doctors recommend intermittent hormonal therapy to men with metastatic prostate cancer, believing it will reduce their risk of side effects
IN THIS ISSUE 7 10
FDA fast tracks galeterone for CRPC treatment Pomegranate extract increases PSA doubling time
Expert Q&A: the urologist who became a medical school dean
High uric acid raises CKD risk in hypertensive patients
Pediatric renal graft survival improves over time Foot ulcers raise mortality risk in diabetic patients on dialysis. PAGE 18
without compromising their outcome, but these findings demonstrate a downside to this approach for certain men,” said lead researcher Maha Hussain, MD, Professor of Medicine and Urology at the University of Michigan Comprehensive Cancer Center in Ann Arbor. “The findings clearly demonstrate that intermittent hormonal therapy is not as effective for all patients with metastatic prostate cancer. These findings are likely practice changing for many doctors in the U.S. and abroad who routinely use intermittent therapy. Specifically, physicians must counsel
Vitamin D Less Effective in Hispanics HISPANICS WITH chronic kidney disease (CKD) and low vitamin D levels respond worse to ergocalciferol therapy than Caucasians, according to new findings. Researchers led by James Wetmore, MD, of the University of Kansas Medical Center in Kansas City, retrospectively analyzed data from 157 Hispanic and 27 Caucasian CKD patients not on dialysis. Low levels of 25-hydroxyvitamin D—25(OH)D—were found in 89.4% of Hispanics compared with 61.4% of Caucasians, despite similar degrees of CKD, according to an online report in International Urology and Nephrology. continued on page 8
Continuous ADT Intermittent ADT
interested patients regarding the potential negative impact on survival with intermittent therapy.” The study enrolled 3,040 men with hormone-sensitive, metastatic prostate cancer between 1995 and 2008. All men received an initial course of
Median survival time (years)
% surviving at least 10 years
© CMSP / K. SOMERVILLE
androgen-deprivation treatment for seven months. The 1,535 eligible men whose PSA level dropped to 4 ng/ mL or less by the end of those seven months were then assigned at random to stop therapy (the intermittent thercontinued on page 8
Ureteroscopy Overtakes SWL BY ROSEMARY FREI, MSc BANFF, Alberta—Ureteroscopy has replaced extracorporeal shockwave lithotripsy (SWL) as the most commonly used treatment for removing kidney stones, according to researchers in Ontario, Canada. Results presented at the Canadian Urological Association’s 2012 annual meeting indicate the use of SWL dropped from 68.5% of all procedures for ureteral stones in 1991 to 33.7% in 2010. Concomitantly, URS use increased from 24.6% to 59.5%. Study leader Michael Ordon, MD, pointed to several possible reasons for this trend, including the development
of smaller, more flexible ureteroscopes with improved optics that have made the technology more accurate and less prone to complications. In addition, the advent of the holmium:YAG laser has made URS and stone fragmentation safer and more efficient. Together, these advancements have led the American Urological Association to recognize both URS and SWL as a first-line treatment options for ureteral stones, he noted. “There is also the fact that more recently trained urologists have gained much more experience and competence in URS during their residency training, thanks to the above advances and as such are more continued on page 8
Earn 1 CME credit in this issue
An Update: Radiation or Surgery for Prostate Cancer PAGE 31
PROSTATE TUMOR TISSUE
Important Safety Information Contraindications—ZYTIGA® may cause fetal harm (Pregnancy Category X) and is contraindicated in women who are or may become pregnant. Hypertension, Hypokalemia, and Fluid Retention Due to Mineralocorticoid Excess—Use with caution in patients with a history of cardiovascular disease or with medical conditions that might be compromised by increases in hypertension, hypokalemia, and fluid retention. ZYTIGA® may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition. Safety has not been established in patients with LVEF < 50% or New York Heart Association (NYHA) Class III or IV heart failure because these patients were excluded from the randomized clinical trial. Control hypertension and correct hypokalemia before and during treatment. Monitor blood pressure, serum potassium, and symptoms of fluid retention at least monthly. Adrenocortical Insufficiency (AI)—AI has been reported in clinical trials in patients receiving ZYTIGA® in combination with prednisone, after an interruption of daily steroids, and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of AI if prednisone is stopped or withdrawn, if prednisone dose is reduced, or if the patient experiences unusual stress. Symptoms and signs of AI may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with ZYTIGA®. Perform appropriate tests, if indicated, to confirm AI.
Increased dosages of corticosteroids may be used before, during, and after stressful situations. Hepatotoxicity—Increases in liver enzymes have led to drug interruption, dose modification, and/or discontinuation. Monitor liver function and modify, withhold, or discontinue ZYTIGA® dosing as recommended (see Prescribing Information for more information). Measure serum transaminases [alanine aminotransferase (ALT) and aspartate aminotransferase (AST)] and bilirubin levels prior to starting treatment with ZYTIGA®, every two weeks for the first three months of treatment, and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the upper limit of normal (ULN) or the bilirubin rises above three times the ULN, interrupt ZYTIGA® treatment and closely monitor liver function. Food Effect—ZYTIGA® must be taken on an empty stomach. Exposure of abiraterone increases up to 10-fold when abiraterone acetate is taken with meals. No food should be eaten for at least two hours before the dose of ZYTIGA® is taken and for at least one hour after the dose of ZYTIGA® is taken. Abiraterone Cmax and AUC 0-∞ (exposure) were increased up to 17- and 10-fold higher, respectively, when a single dose of abiraterone acetate was administered with a meal compared to a fasted state.
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ZYTIGA® is converted in vivo to abiraterone, an androgen biosynthesis inhibitor (ABI) that directly affects the androgen biosynthesis pathway by inhibiting CYP17 (17␣-hydroxylase/C17,20-lyase) — Consequently, androgen biosynthesis is inhibited at 3 sources of testosterone production: the testes, adrenal glands, and prostate tumor tissue Androgen biosynthesis inhibition with ZYTIGA® results in decreased levels of serum testosterone and other androgens
Proven survival benefit Results of the interim analysis of the pivotal phase 3 study*† showed a statistically significant improvement in overall survival (OS) in patients treated with ZYTIGA® plus prednisone compared with patients who received placebo plus prednisone (median OS: 14.8 months vs 10.9 months [hazard ratio (HR) = 0.646; 95% confidence interval (CI): 0.543, 0.768; P < 0.0001]) — This represents a 3.9-month difference/improvement in median OS In an updated analysis,‡ results were consistent with the interim analysis, with a 4.6-month difference/improvement in median OS with ZYTIGA® plus prednisone compared with placebo plus prednisone (median OS: 15.8 months vs 11.2 months [HR = 0.74; 95% CI: 0.638, 0.859])
ZYTIGA® (abiraterone acetate) in combination with prednisone is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) who have received prior chemotherapy containing docetaxel.
Adverse Reactions—The most common adverse reactions (≥ 5%) are joint swelling or discomfort, hypokalemia, edema, muscle discomfort, hot flush, diarrhea, urinary tract infection, cough, hypertension, arrhythmia, urinary frequency, nocturia, dyspepsia, fractures and upper respiratory tract infection. Drug Interactions—ZYTIGA® is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. Avoid coadministration with CYP2D6 substrates that have a narrow therapeutic index. If an alternative cannot be used, exercise caution and consider a dose reduction of the CYP2D6 substrate. Additionally, abiraterone is a substrate of CYP3A4 in vitro. Strong inhibitors and inducers of CYP3A4 should be avoided or used with caution. Use in Specific Populations—The safety of ZYTIGA® in patients with baseline severe hepatic impairment has not been studied. These patients should not receive ZYTIGA®. *Study Design: ZYTIGA®, in combination with prednisone, was evaluated in a phase 3, randomized, double-blind, placebo-controlled, multicenter
Janssen Biotech, Inc. © Janssen Biotech, Inc. 2012 3/12 08Z12069B
study in patients with metastatic castration-resistant prostate cancer (mCRPC) who had received prior chemotherapy containing docetaxel (N = 1,195). Patients were randomized 2:1 to receive ZYTIGA® 1,000 mg orally once daily + prednisone 5 mg orally twice daily (n = 797) or placebo orally once daily + prednisone 5 mg orally twice daily (n = 398). Patients were using a gonadotropin-releasing hormone (GnRH) agonist or were previously treated with orchiectomy and were at castration levels of testosterone (serum testosterone ≤ 50 ng/dL).1 The primary efficacy endpoint was overall survival. †552 events. ‡775 events. 08Z11121R3
Mechanism of action
Reference: 1. de Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011;364(21):1995-2005.
Please see adjacent pages for brief summary of full Prescribing Information.
ZYTIGA® (abiraterone acetate) Tablets Brief Summary of Prescribing Information. INDICATIONS AND USAGE ZYTIGA in combination with prednisone is indicated for the treatment of patients with metastatic castrationresistant prostate cancer (CRPC) who have received prior chemotherapy containing docetaxel. CONTRAINDICATIONS Pregnancy: ZYTIGA may cause fetal harm when administered to a pregnant woman. ZYTIGA is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. WARNINGS AND PRECAUTIONS Hypertension, Hypokalemia and Fluid Retention Due to Mineralocorticoid Excess: Use ZYTIGA with caution in patients with a history of cardiovascular disease. ZYTIGA may cause hypertension, hypokalemia, and ﬂuid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition [see Adverse Reactions and Clinical Pharmacology (12.1) in full Prescribing Information]. Co-administration of a corticosteroid suppresses adrenocorticotropic hormone (ACTH) drive, resulting in a reduction in the incidence and severity of these adverse reactions. Use caution when treating patients whose underlying medical conditions might be compromised by increases in blood pressure, hypokalemia or ﬂuid retention, e.g., those with heart failure, recent myocardial infarction or ventricular arrhythmia. The safety of ZYTIGA in patients with left ventricular ejection fraction <50% or NYHA Class III or IV heart failure has not been established because these patients were excluded from the randomized clinical trial. Monitor patients for hypertension, hypokalemia, and ﬂuid retention at least once a month. Control hypertension and correct hypokalemia before and during treatment with ZYTIGA. Adrenocortical Insufﬁciency: Adrenocortical insufﬁciency has been reported in clinical trials in patients receiving ZYTIGA in combination with prednisone, following interruption of daily steroids and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of adrenocortical insufﬁciency, particularly if patients are withdrawn from prednisone, have prednisone dose reductions, or experience unusual stress. Symptoms and signs of adrenocortical insufﬁciency may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with ZYTIGA. If clinically indicated, perform appropriate tests to conﬁrm the diagnosis of adrenocortical insufﬁciency. Increased dosage of corticosteroids may be indicated before, during and after stressful situations [see Warnings and Precautions]. Hepatotoxicity: Marked increases in liver enzymes leading to drug discontinuation or dosage modiﬁcation have occurred [see Adverse Reactions]. Measure serum transaminases (ALT and AST) and bilirubin levels prior to starting treatment with ZYTIGA, every two weeks for the ﬁrst three months of treatment and monthly thereafter. In patients with baseline moderate hepatic impairment receiving a reduced ZYTIGA dose of 250 mg, measure ALT, AST, and bilirubin prior to the start of treatment, every week for the ﬁrst month, every two weeks for the following two months of treatment and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above ﬁve times the ULN, or the bilirubin rises above three times the ULN, interrupt ZYTIGA treatment and closely monitor liver function. Re-treatment with ZYTIGA at a reduced dose level may take place only after return of liver function tests to the patient’s baseline or to AST and ALT less than or equal to 2.5X ULN and total bilirubin less than or equal to 1.5X ULN [see Dosage and Administration (2.2) in full Prescribing Information]. The safety of ZYTIGA re-treatment of patients who develop AST or ALT greater than or equal to 20X ULN and/or bilirubin greater than or equal to 10X ULN is unknown. Food Effect: ZYTIGA must be taken on an empty stomach. No food should be consumed for at least two hours before the dose of ZYTIGA is taken and for at least one hour after the dose of ZYTIGA is taken. Abiraterone Cmax and AUC0-∞ (exposure) were increased up to 17- and 10-fold higher, respectively, when a single dose of abiraterone acetate was administered with a meal compared to a fasted state. The safety of these increased exposures when multiple doses of abiraterone acetate are taken with food has not been assessed [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information]. ADVERSE REACTIONS The following are discussed in more detail in other sections of the labeling: Hypertension, hypokalemia, and ﬂuid retention due to mineralocorticoid excess [see Warnings and Precautions]. Adrenocortical insufﬁciency [see Warnings and Precautions]. Hepatotoxicity [see Warnings and Precautions]. Food effect [see Warnings and Precautions]. Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reﬂect the rates observed in clinical practice. In a placebo-controlled, multicenter phase 3 clinical trial of patients with metastatic castration-resistant prostate cancer who were using a gonadotropin-releasing hormone (GnRH) agonist or were previously treated with orchiectomy, ZYTIGA was administered at a dose of 1,000 mg daily in combination with prednisone 5 mg twice daily in the active treatment arm (N = 791). Placebo plus prednisone 5 mg twice daily was given to control patients (N = 394). The median duration of treatment with ZYTIGA was 8 months. The most common adverse drug reactions (≥5%) reported in clinical studies were joint swelling or discomfort, hypokalemia, edema, muscle discomfort, hot ﬂush, diarrhea, urinary tract infection, cough, hypertension, arrhythmia, urinary frequency, nocturia, dyspepsia, fractures and upper respiratory tract infection. The most common adverse drug reactions that resulted in drug discontinuation were aspartate aminotransferase increased, alanine aminotransferase increased, urosepsis and cardiac failure (each in <1% of patients taking ZYTIGA). Adverse reactions and laboratory abnormalities related to mineralocorticoid effects were reported more commonly in patients treated with ZYTIGA than in patients treated with placebo: hypokalemia 28% versus 20%, hypertension 9% versus 7% and ﬂuid retention (edema) 27% versus 18%, respectively (see Table 1). In patients treated with ZYTIGA, grades 3 to 4 hypokalemia occurred in 5% of patients and grades 3 to 4 hypertension was reported in 1% of patients [see Warnings and Precautions]. Table 1 shows adverse reactions due to ZYTIGA that occurred with either a ≥ 2% absolute increase in frequency compared to placebo, or were events of special interest (mineralocorticoid excess, cardiac adverse reactions, and liver toxicities). Table 1: Adverse Reactions due to ZYTIGA in a Placebo-Controlled Phase 3 Trial ZYTIGA with Prednisone (N=791) System/Organ Class All Grades1 Grade 3-4 Adverse reaction % % Musculoskeletal and connective tissue disorders 29.5 4.2 Joint swelling/discomfort2 26.2 3.0 Muscle discomfort3 General disorders 26.7 1.9 Edema4 Vascular disorders Hot ﬂush 19.0 0.3 Hypertension 8.5 1.3 Gastrointestinal disorders Diarrhea 17.6 0.6 Dyspepsia 6.1 0 Infections and infestations Urinary tract infection 11.5 2.1 Upper respiratory tract infection 5.4 0 Respiratory, thoracic and mediastinal disorders Cough 10.6 0 Renal and urinary disorders Urinary frequency 7.2 0.3 Nocturia 6.2 0 Injury, poisoning and procedural complications 5.9 1.4 Fractures5 Cardiac disorders Arrhythmia6 7.2 1.1 Chest pain or chest discomfort 7 3.8 0.5 Cardiac failure8 2.3 1.9 1 2 3
Placebo with Prednisone (N=394) All Grades Grade 3-4 % % 23.4 23.1
4.6 2.8 1.0
1.0 0 0.3
Adverse events graded according to CTCAE version 3.0 Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness Includes terms Muscle spasms, Musculoskeletal pain, Myalgia, Musculoskeletal discomfort, and Musculoskeletal stiffness
ZYTIGA® (abiraterone acetate) Tablets 4 5 6
Includes terms Edema, Edema peripheral, Pitting edema, and Generalized edema Includes all fractures with the exception of pathological fracture Includes terms Arrhythmia, Tachycardia, Atrial ﬁbrillation, Supraventricular tachycardia, Atrial tachycardia, Ventricular tachycardia, Atrial ﬂutter, Bradycardia, Atrioventricular block complete, Conduction disorder, and Bradyarrhythmia 7 Includes terms Angina pectoris, Chest pain, and Angina unstable. Myocardial infarction or ischemia occurred more commonly in the placebo arm than in the ZYTIGA arm (1.3% vs. 1.1% respectively). 8 Includes terms Cardiac failure, Cardiac failure congestive, Left ventricular dysfunction, Cardiogenic shock, Cardiomegaly, Cardiomyopathy, and Ejection fraction decreased Cardiovascular Adverse Reactions: Cardiovascular adverse reactions in the phase 3 trial are shown in Table 1. The majority of arrhythmias were grade 1 or 2. Grade 3-4 arrhythmias occurred at similar rates in the two arms. There was one death associated with arrhythmia and one patient with sudden death in the ZYTIGA arm. No patients had sudden death or arrhythmia associated with death in the placebo arm. Cardiac ischemia or myocardial infarction led to death in 2 patients in the placebo arm and 1 death in the ZYTIGA arm. Cardiac failure resulting in death occurred in 1 patient on both arms. Hepatotoxicity: Drug-associated hepatotoxicity with elevated ALT, AST, and total bilirubin has been reported in patients treated with ZYTIGA. Across all clinical trials, liver function test elevations (ALT or AST increases of > 5X ULN) were reported in 2.3% of patients who received ZYTIGA, typically during the ﬁrst 3 months after starting treatment. In the phase 3 trial, patients whose baseline ALT or AST were elevated were more likely to experience liver function test elevations than those beginning with normal values. When elevations of either ALT or AST > 5X ULN, or elevations in bilirubin > 3X ULN were observed, ZYTIGA was withheld or discontinued. In two instances marked increases in liver function tests occurred [see Warnings and Precautions]. These two patients with normal baseline hepatic function, experienced ALT or AST elevations 15 to 40X ULN and bilirubin elevations 2 to 6 X ULN. Upon discontinuation of ZYTIGA, both patients had normalization of their liver function tests and one patient was re-treated with ZYTIGA without recurrence of the elevations. In clinical trials, the following patients were excluded: patients with active hepatitis, patients with baseline ALT and/or AST ≥ 2.5X ULN in the absence of liver metastases, and patients with ALT and/or AST > 5X ULN in the presence of liver metastases. Abnormal liver function tests developing in patients participating in clinical trials were managed by treatment interruption, dose modiﬁcation and/or discontinuation [see Dosage and Administration (2.2) in full Prescribing Information and Warnings and Precautions]. Patients with elevations of ALT or AST > 20X ULN were not re-treated. Other Adverse Reactions: Adrenal insufﬁciency occurred in two patients on the abiraterone arm of the phase 3 clinical trial (< 1%). Laboratory Abnormalities of Interest: Table 2 shows laboratory values of interest from the phase 3 placebocontrolled clinical trial. Grade 3-4 low serum phosphate (7.2%) and potassium (5.3%) occurred more frequently in the ZYTIGA arm. Table 2: Laboratory Abnormalities of Interest in a Phase 3 Placebo-Controlled Clinical Trial Abiraterone (N=791) Placebo (N=394) All Grades Grade 3-4 All Grades Grade 3-4 Laboratory Abnormality (%) (%) (%) (%) High Triglyceride 62.5 0.4 53.0 0 High AST 30.6 2.1 36.3 1.5 Low Potassium 28.3 5.3 19.8 1.0 Low Phosphorus 23.8 7.2 15.7 5.8 High ALT 11.1 1.4 10.4 0.8 High Total Bilirubin 6.6 0.1 4.6 0 DRUG INTERACTIONS Effects of Abiraterone on Drug Metabolizing Enzymes: ZYTIGA is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. In a CYP2D6 drug-drug interaction trial, the Cmax and AUC of dextromethorphan (CYP2D6 substrate) were increased 2.8- and 2.9-fold, respectively, when dextromethorphan was given with abiraterone acetate 1,000 mg daily and prednisone 5 mg twice daily. Avoid co-administration of abiraterone acetate with substrates of CYP2D6 with a narrow therapeutic index (e.g., thioridazine). If alternative treatments cannot be used, exercise caution and consider a dose reduction of the concomitant CYP2D6 substrate drug [see Clinical Pharmacology (12.3) in full Prescribing Information]. In vitro, ZYTIGA was shown to inhibit the hepatic drug-metabolizing enzyme CYP2C8. There are no clinical data on the use of ZYTIGA with drugs that are substrates of CYP2C8. Drugs that Inhibit or Induce CYP3A4 Enzymes: Based on in vitro data, ZYTIGA is a substrate of CYP3A4. The effects of strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelﬁnavir, voriconazole) or inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) on the pharmacokinetics of abiraterone have not been evaluated, in vivo. Avoid or use with caution, strong inhibitors and inducers of CYP3A4 during ZYTIGA treatment [see Clinical Pharmacology (12.3) in full Prescribing Information]. USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category X [see Contraindications]. ZYTIGA is contraindicated in women who are or may become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus and the potential risk for pregnancy loss. Women of childbearing potential should be advised to avoid becoming pregnant during treatment with ZYTIGA. Nursing Mothers: ZYTIGA is not indicated for use in women. It is not known if abiraterone acetate is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from ZYTIGA, a decision should be made to either discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother. Pediatric Use: ZYTIGA is not indicated in children. Geriatric Use: Of the total number of patients in a phase 3 trial of ZYTIGA, 71% of patients were 65 years and over and 28% were 75 years and over. No overall differences in safety or effectiveness were observed between these elderly patients and younger patients. Patients with Hepatic Impairment: The pharmacokinetics of abiraterone were examined in subjects with baseline mild (n = 8) or moderate (n = 8) hepatic impairment (Child-Pugh Class A and B, respectively) and in 8 healthy control subjects with normal hepatic function. The systemic exposure (AUC) of abiraterone after a single oral 1,000 mg dose of ZYTIGA increased by approximately 1.1-fold and 3.6-fold in subjects with mild and moderate baseline hepatic impairment, respectively compared to subjects with normal hepatic function. No dosage adjustment is necessary for patients with baseline mild hepatic impairment. In patients with baseline moderate hepatic impairment (Child-Pugh Class B), reduce the recommended dose of ZYTIGA to 250 mg once daily. If elevations in ALT or AST >5X ULN or total bilirubin >3X ULN occur in patients with baseline moderate hepatic impairment, discontinue ZYTIGA treatment [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information]. The safety of ZYTIGA in patients with baseline severe hepatic impairment has not been studied. These patients should not receive ZYTIGA. For patients who develop hepatotoxicity during treatment, interruption of treatment and dosage adjustment may be required [see Dosage and Administration (2.2) in full Prescribing Information, Warnings and Precautions, and Clinical Pharmacology (12.3) in full Prescribing Information]. Patients with Renal Impairment: In a dedicated renal impairment trial, the mean PK parameters were comparable between healthy subjects with normal renal function (N=8) and those with end stage renal disease (ESRD) on hemodialysis (N=8) after a single oral 1,000 mg dose of ZYTIGA. No dosage adjustment is necessary for patients with renal impairment [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information]. OVERDOSAGE: There have been no reports of overdose of ZYTIGA during clinical studies. There is no speciﬁc antidote. In the event of an overdose, stop ZYTIGA, undertake general supportive measures, including monitoring for arrhythmias and cardiac failure and assess liver function. Storage and Handling: Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP controlled room temperature]. Based on its mechanism of action, ZYTIGA may harm a developing fetus. Therefore, women who are pregnant or women who may be pregnant should not handle ZYTIGA without protection, e.g., gloves [see Use in Speciﬁc Populations]. Manufactured by: Patheon Inc. Mississauga, Canada
Manufactured for: Janssen Biotech, Inc. Horsham, PA 19044
Issued: May 2012
Renal & Urology News 5
FROM THE MEDICAL DIRECTOR EDITORIAL ADVISORY BOARD
How About Twice-Weekly Hemodialysis?
n recent trips to India, China, Brazil, and other countries, I was intrigued by large numbers of patients with end-stage renal disease who underwent hemodialysis (HD) less frequently than three times a week. Indeed, I encountered sporadic patients who received HD as infrequently as only once to twice a month! Dialysis treatment time could be as short as two to three hours per session. I was told that these patients would usually do well, especially because most of them have decent residual renal function with good urine output. Some Chinese nephrologists are even proud that by offering infrequent and short HD treatments, they preserve patients’ residual renal function for a longer time, similar to what we consider a main advantage of peritoneal dialysis. In the United States, we feel that patients deserve an “adequate” dialysis treatment dose, at least three times a week, with each session lasting three to four hours. Western European countries and Japan usually follow our lead. Some French nephrology centers offer five to eight hours of HD three times a week. Although some opinion leaders suggest even higher dialysis doses such as daily or long nocturnal HD, convincing data to show whether short and infrequent dialysis is significantly inferior are lacking. While I do not dispute the potential role of finances and resource constraints in making infrequent dialysis so prevalent in some countries, this practice may offer unique opportunities to learn. Many Indian and Chinese nephrologists are more aggressive than their American counterparts with regard to strategies to preserve residual renal function with low- to very low-protein diets combined with essential amino acids or their keto-analogues. Given the heightened discussion of early versus late dialysis initiation and recent data questioning the wisdom of early dialysis start, it is time to explore alternatives. In my opinion, it never makes sense that patients with chronic kidney disease suddenly need to start full-blown dialysis treatment. In the same way that worsening kidney function happens gradually, perhaps offering dialysis treatment should also be gradual, starting from one HD treatment a week, or as necessary. We keep a freshly transplanted patient “on the wet side” to keep the new kidney well perfused, so maybe we should be more conservative with the native kidneys and avoid excessive diuresis or frequent HD and its associated circulatory compromise during the first few months of therapy. Though these fundamental questions have not been raised before, I would say it is never too late to start. Kamyar Kalantar-Zadeh, MD, MPH, PhD Professor & Chief Division of Nephrology & Hypertension University of California Irvine School of Medicine Orange, Calif.
Renal & Urology News welcomes letters to the editor. Send to: Jody A. Charnow, 114 West 26th Street, 4th Floor, New York, NY 10001 or e-mail email@example.com
Medical Director, Urology
Medical Director, Nephrology
Robert G. Uzzo, MD, FACS G. Willing “Wing” Pepper Chair in Cancer Research Professor and Chairman Department of Surgery Fox Chase Cancer Center Temple University School of Medicine Philadelphia
Kamyar Kalantar-Zadeh, MD, MPH, PhD Medical Director, Nephrology Professor & Chief Division of Nephrology & Hypertension University of California Irvine School of Medicine Orange, Calif.
Nephrologists Urologists Frank R. Cerniglia Jr, MD Attending Pediatric Urologist Children’s Urology of Virginia Richmond, Va. Christopher S. Cooper, MD Director, Pediatric Urology Children’s Hospital of Iowa Iowa City R. John Honey, MD Head, Division of Urology, Endourology/Kidney Stone Diseases St. Michael’s Hospital University of Toronto Stanton Honig, MD Associate Clinical Professor of Surgery/Urology University of Connecticut School of Medicine, Urology Center New Haven J. Stephen Jones, MD, FACS Chairman Department of Regional Urology Cleveland Clinic Glickman Urological & Kidney Institute Professor of Surgery Cleveland Clinic Lerner College of Medicine of Case Western Reserve University James M. McKiernan, MD Assistant Professor of Urology Columbia University College of Physicians and Surgeons New York City Kenneth Pace, MD, MSc, FRCSC Assistant Professor Division of Urology St. Michael’s Hospital University of Toronto Ryan F. Paterson, MD, FRCSC Assistant Professor Division of Urologic Sciences University of British Columbia Vancouver, Canada
Anthony J. Bleyer, MD, MS Professor of Internal Medicine/Nephrology Wake Forest University School of Medicine Winston-Salem, N.C. Suphamai Bunnapradist, MD Director of Research Department of Nephrology Kidney Transplant Research Center The David Geffen School of Medicine at UCLA R. Michael Hofmann, MD Associate Professor and Medical Director, Living Kidney Donor Program University of Wisconsin School of Medicine and Public Health, Madison Csaba P. Kovesdy, MD Associate Professor of Clinical Medicine University of Virginia, Charlottesville Chief of Nephrology Salem VA Medical Center Salem, Va. Edgar V. Lerma, MD, FACP, FASN, FAHA Clinical Associate Professor of Medicine Section of Nephrology Department of Medicine University of Illinois at Chicago College of Medicine, Chicago Allen Nissenson, MD Emeritus Professor of Medicine The David Geffen School of Medicine at UCLA, Chief Medical Officer, DaVita Inc. Rulan Parekh, MD, MS Associate Professor Johns Hopkins Children’s Center, Baltimore Robert Provenzano, MD Chief, Section of Nephrology St. John Hospital and Medical Center, Detroit Robert S. Rigolosi, MD Director, Regional Hemodialysis Center Holy Name Hospital, Teaneck, N.J. Lynda Anne Szczech, MD, MSCE Medical Director, Pharmacovigilence and Global Product Development, PPD, Inc. Morrisville, N.C.
Renal & Urology News Staff Editor Executive editor Senior editor Web editor Editorial coordinator Art director Group art director, Haymarket Medical VP, audience development and operations Production assistant Group production manager Product manager, digital products Circulation manager National accounts manager Editorial director Publisher VP medical magazines and digital products CEO, Haymarket Media Inc.
Jody A. Charnow Marina Galanakis Delicia Honen Yard Stephan Cho Candy Iemma Andrew Bass Jennifer Dvoretz John Crewe Brian Wask Kathleen Millea Chris Bubeck Paul Silver William Canning Jeff Forster Dominic Barone Jim Burke Lee Maniscalco
Renal & Urology News (ISSN 1550-9478) Volume 11, Number 8. Published monthly by Haymarket Media, Inc., 114 West 26th Street, 4th Floor, New York, NY 10001. Periodicals postage paid at New York, NY, and an additional mailing office. The subscription rates for one year are, in the U.S., $75.00; in Canada, $85.00; all other foreign countries, $110.00. Single issues, $20.00. www.renalandurologynews.com. Postmaster: Send address changes to Renal & Urology News, c/o DMD Data Inc., 2340 River Road, Des Plaines, IL 60018. For reprints, contact Wright’s Reprints at 1.877.652.5295. Copyright: All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means (electronic, mechanical, photocopying, recording, or otherwise) without the prior written permission of Haymarket Media, Inc. Copyright © 2012.
VOLUME 11, ISSUE NUMBER 8
this month at renalandurologynews.com Expert Q&A Yoshio Hall, MD, of the University of Washington, Seattle, discusses his recent study showing that frequent in-center hemodialysis does not significantly improve objective physical performance.
Sorafenib, Sunitinib Safe for the Heart Adjuvant use of either drug in patients with resected renal cell carcinoma did not increase the risk of cardiac events.
Earlier Abiraterone Use Shows Promise Combined with leuprolide, it eliminated or nearly eliminated prostate cancer in some patients.
Clinical Quiz Take our latest quiz at renalandurologynews.com /clinical-quiz/. Answer correctly and you will be entered to win a $50 American Express gift card.
Practice Management Patient surveys can provide information useful to a practice
CME Feature 31
An Update: Radiation or Surgery for Prostate Cancer Stephen A. Boorjian, MD, Associate Professor in the Department of Urology at the Mayo Clinic in Rochester, Minn., reviews studies of comparative outcomes for each approach, particularly in patients with high-risk disease.
Vasculitis Patients’ Treatment Knowledge Lacking Patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis have substantial knowledge deficits about potential treatment-related adverse effects.
Diabetic Foot Ulcers Raise Death Risk Patients with an active foot ulcer at study enrollment had a 119% increase in the risk of death.
The Medical Minute Visit renalandurologynews.com /the-medical-minute/ to hear podcast reports on new studies. Our latest include: • ADT Plus Radiation Improves Outcomes in PCa Patients • Program May Encourage Living Donors to Give a Kidney • “Firefly” May Aid Kidney Cancer Surgery • Help for Men with Peyronie's Disease • Women Fare Better than Men Post-Nephrectomy
RP Suitable for High-Risk Localized PCa Radical prostatectomy for very high-risk locally advanced prostate cancer, with or without adjuvant or neoadjuvant treatment, can provide “very satisfactory” outcomes.
Higher Binder Dose Improves Phosphorus Lowering Raising the dose of lanthanum carbonate from a lower conventionally used dose may improve phosphorus control in patients with chronic kidney disease and hyperphosphatemia. Renal Graft Loss Down in Children Pediatric renal graft survival has improved over time. The 10-year graft survival was 55.5% for transplant performed in 2010 versus 44.5% for those performed in 1987.
Pomegranate Extract Found to Increase PSADT Men with rising PSA following initial therapy for localized prostate cancer had an increase in PSA doubling time after being treated with pomegranate extract.
It is possible that long-term use of [calcium and
vitamin D] supplements causes hypercalciuria and hypercalcemia, and this can contribute to kidney stones.
See our story on page 13
From the Medical Director How about twice-weekly hemodialysis?
News in Brief Pay increase proposed for ESRD centers
On the Forefront Nephrectomy or dialysis?
Renal Nutrition Update Benefits of plant protein
Practice Management Transitioning to ICD-10
Your Money Fundamental index funds
Malpractice Doctors win most lawsuits
Renal & Urology News 7
News in Brief Please visit us at www.renalandurologynews.com for the latest news updates from the fields of urology and nephrology
Short Takes FDA Puts CRPC Drug on Fast Track
hypertension, and 33% had diabetes,
The FDA has given fast-track designa-
Journal of Medicine 2012;125:679-
tion to galeterone (TOK-001), a small
687.e1) “These findings from the latest
molecule, oral drug for the treatment
nationally representative data highlight
of castrate-resistant prostate cancer
remarkable prevalences and population
estimates of comorbidities of gout and
In the phase 1 ARMOR (Androgen
according to a report in The American
hyperuricemia in the U.S.,” the authors
Receptor Modulation Optimized for
concluded. “Appropriate preventive
Response) study, galeterone demon-
and management measures of these
strated efficacy and was well tolerated
comorbidities should be implemented
in CRPC patients. Galeterone works
in gout management, with a preference
by preventing testosterone synthesis,
to strategies that can improve gout and
antagonizing testosterone binding to
the androgen receptor, and degrading the androgen receptor protein. Developed by Tokai Pharmaceuticals
Selenium May Lower Prostate Cancer Risk
in Cambridge, Mass., the drug will
A meta-analysis of 12 studies with
enter a phase 2 trial later this year.
a total of 13,254 participants and 5,007 cases of prostate cancer (PCa) showed that prostate cancer (PCa) risk
Data from 5,707 participants of the Na-
rum selenium up to 170 ng/mL. Three
tional Health and Nutrition Examination
high-quality studies of toenail selenium
Survey (NHANES) 2007–2008 show
and cancer risk indicated a reduction
that gout now affects 4% of Americans
in prostate cancer risk (estimated
(8.3 million individuals), and hyperurice-
relative risk: 0.29) with a toenail sele-
mia, 21% (43.3 million). Among those in
nium concentration between 0.85 and
the top serum urate category—greater
0.94 µg/g, investigators reported
than 4 mg/dL—86% had stage 2 or
in The American Journal of Clinical
higher chronic kidney disease, 66% had
fro St m ra ig t h ht eW eb
Study: Gout Affects 4% of Americans
decreased with increasing plasma/se-
Affordable Care Act and Patient Care
Now that the U.S. S Supreme Court has upheld P President Obama's national health law (popularly referred to as “Obamacare”), Renal & Urology News asked urologists and nephrologists the following question: “Overall, do you think ‘Obamacare’ will improve patient care?” Here are the results from 241 respondents.
New Equation Could More Accurately Diagnose CKD A
new equation that uses both creatinine and cystatin C measurements provides a more accurate estimate of kidney function than either marker alone, according to a new study that included data from diverse populations totaling 5,352 participants across 13 studies. The equation may be useful as a confirmatory test for CKD. Among subjects with an estimated glomerular filtrate rate (eGFR) of 45 to 74 mL/min/1.73m2 based on creatinine alone, the combined equation improved the classification of measured GFR as either less than 60 or 60 or greater (net reclassification index, 19.4%), and correctly reclassified 16.9% of those with eGFR of 45 to 59 as having a GFR of at least 60, according to findings published in the New England Journal of Medicine (2012;367:20-29).
CRP May Predict Sunitinib Response in RCC Patients C
-reactive protein (CRP) is a significant prognostic indicator in patients with advanced renal cell carcinoma (RCC) treated with sunitinib, according to Japanese researchers. “Pretreatment CRP level could be a useful biomarker for response to sunitinib treatment,” the authors concluded in the International Journal of Urology (published online ahead of print). Tetsuo Fujita, MD, and colleagues at Kitasato University School of Medicine, Sagamihara, Kanagawa, studied 41 patients with advanced clear-cell RCC treated with sunitinib. Of these, 11 (26.8%) showed a partial response to treatment and 10 (24.4%) had stable disease. Patients with normal CRP levels (30 mg/dL or less) had a significantly higher rate of partial response and stable disease (84.6% vs. 35.7%) and significantly longer progression-free survival (median 19 vs. 6 months) than patients with elevated CRP levels.
CMS Proposes Increased Pay to ESRD Facilities T
*Percentages do not add up to 100% because of rounding.
he Centers for Medicare & Medicaid Services (CMS) has proposed a rule that would boost payments for facilities that provide care for patients with end-stage renal disease (ESRD). Payment rates are expected to rise by 2.5% in 2013, according to a CMS press release. CMS estimates that Medicare payments to the 5,633 ESRD facilities will total $8.7 billion in 2013. The proposed rule, which appeared in the July 11 Federal Register, also would update Medicare policies and strengthen incentives for improved quality of care and better outcomes for patients through improvements to the ESRD Quality Initiative Program. When all policy changes are considered together, payments to ESRD facilities are anticipated to rise by 3.1% in 2013, according to CMS. According to CMS, the proposed rule would continue to focus on clinical measures and expand the scope of the reporting measures included in the ESRD Quality Incentive Program “to encompass a broader range of patient populations who receive dialysis care and to address concerns about the quality of life experienced by patients on dialysis."
8 Renal & Urology News
Intermittent ADT inferior continued from page 1
apy group) or continue therapy (the continuous therapy group). Those randomized to the intermittent therapy arm had their treatment suspended until their PSA rose to a predetermined level, at which time they started another seven-month course of ADT. The patients cycled on and off therapy in this way as long as their PSA levels continued to respond appropriately during the “on” cycle.
Survival differences The 1,535 eligible patients had a median age of 70 years; 48% had extensive disease and 12% had received prior neoadjuvant ADT. A total of 765 were randomized to continuous therapy and 770 patients were randomized to the intermittent arm. Men on continuous therapy had a median overall survival time of 5.8 years from the time of randomization, with 29% of these men surviving at least 10 years. Those on
Ureteroscopy/SWL continued from page 1
likely to utilize it once out in independent practice,” said Dr. Ordon, an endourology and minimally invasive surgery fellow at St. Michael’s Hospital and the University of Toronto. “And, specific to Ontario, only three lithotripters are available in the province. Therefore, because of both ease of access and the recognition of URS as a first-line treatment option, many urologists will offer their patients URS instead of SWL.” While urologists are well aware of the trend to much more URS use, most studies corroborating the anecdotal observations have been physician surveys or single-center series. Many of the studies of URS—which also have documented the efficacy of the approach and low retreatment and complication rates— have involved high-volume centers.
intermittent therapy had a median overall survival time of 5.1 years, with 23% surviving at least 10 years from randomization. Additional exploratory subgroup analyses of these new data indicated that after a median follow-up of 9.2 years, the median overall survival time for those with minimal disease (disease that had not spread beyond the lymph nodes or the bones of the spine or pelvis) was 7.1 years on continuous ADT compared with only 5.2 years on intermittent treatment. Patients with extensive disease had median overall survival times of 4.4 years on continuous therapy and 5.0 years on intermittent therapy. There was no evidence that the treatment effect differed by race. The study showed that Grade 3/4 related adverse events were similar for intermittent and continuous treatment (30.3% vs. 32.6%). “In the past, when it came to using hormone therapy in this disease, doctors viewed the disease as one entity and adopted a ‘one size fits all’ approach,” Dr. Hussain said. “Based on this study’s It is for these reasons that Dr. Ordon and other researchers in Toronto evaluateD population-based trends in the treatment of kidney stones. The goal was to objectively document the significant shift from SWL to URS. Not only did the team verify the change, they also observed a constant rate of percutaneous nephrolithotomy (PCNL) over the 20-year period. In addition, they confirmed a significant decrease over time in the need for ancillary or repeat treatment (23.1% vs. 15.3% of procedures), a trend related to the fact that URS was associated with less retreatment than SWL (10.6%13% vs. 22%-30%). However, Dr. Ordon’s group observed an increase in hospital readmissions within seven days of treatment (7.27%10.8%) due to higher readmission rates with URS than SWL (12%-14% vs. 4%-8%). ■
Lithotripsy Use Declining Canadian data show that the proportion of kidney stone cases treated with shock wave lithotripsy declined substantially from 1991 to 2010 such that ureteroscopy is now used in the majority of cases. Shock wave lithotripsy 80
70 60 50
40 30 20 10 0
Source: Ordon M, et al. Data presented at the Canadian Urological Association annual meeting, Banff, Alberta, June 24, Abstract POD-01.01.
findings, it seems that one size does not necessarily fit all.” Intermittent ADT appeared to be safe in prior studies, but those studies generally included either men whose only evidence of prostate cancer progression was an increase in PSA level (as opposed to radiographic evidence of disease spread), or men with wideranging stages of disease (not just metastatic cancer). With respect to quality of life measures, which were compared during the first 15 months following randomization, more men receiving intermittent rather than continuous therapy had significant improvements in the level of sexual functioning..
Durability the issue “There is some improvement in aspects of quality of life, but the durability is the issue,” Dr. Hussain told Renal & Urology News. “Our study demonstrates that what may appear safe may not be completely so, and it sometimes takes a large study to determine this.
Vitamin D less effective continued from page 1
Despite treatment with ergocalciferol in accordance with guidelines from the Kidney Disease Outcomes Quality Initiative (KDOQI), 85.5% of treated Hispanics and 66.7% of treated Caucasians remained vitamin D deficient. Both Hispanics and Caucasians had significant increases in 25(OH)D levels, but the absolute changes were modest (5.0 and 8.0 ng/mL, respectively). The increase observed in Caucasians was significantly greater than in Hispanics, the study showed. Hispanic ethnicity remained independently associated with poorer treatment response even after adjusting for other factors. Dr. Wetmore’s team said their findings suggest that the KDOQI protocol provides inadequate 25(OH)D repletion in many patients with CKD and that alternative approaches may be required.
‘Sobering warning’ “Our findings are a sobering warning to physicians not to have unrealistic expectations about the effectiveness of repletion,” Dr. Wetmore and his colleagues wrote. They also observed that their findings “may have implications for other darker-skinned populations, even in solar-rich environments.” Study participants were drawn from a community nephrology practice in
It’s important to look beyond PSA responses when evaluating hormone therapy approaches and also it’s important to have a control group in performing the trials.” Even though these data showed potential quality of life improvements with intermittent therapy, the primary findings of the study demonstrate that intermittent therapy is inferior with regard to overall survival, which should be the primary consideration when counseling all patients interested in intermittent therapy, , she said. “This clinical trial will change the use of intermittent therapy,” said study co-investigator E. David Crawford, MD, Professor of Surgery/Urology/ Radiation Oncology at the University of Colorado in Denver. “This is the largest study to date and one we have all been waiting for. It shows that intermittent therapy is inferior to standard continuous androgen ablation. There were flaws in other trials such as not powered to show equivalence or even slight but significant differences.” ■
a part of southern Texas that had 226 and 205 clear sunny days in 2006 and 2007, respectively, and is considered a “sunny area” by the U.S. National Weather Center. “On an absolute scale, we had initially expected the latitude of our study site would have resulted in higher 25(OH)D levels in both races than were actually observed,” the authors wrote. They pointed out, however, that in a study comparing the relationship of 25(OH)D levels in CKD patients across many different U.S. geographic
KDOQI guidelines for ergocalciferol treatment may not be sufficient. areas (Am J Kidney Dis 2005;45:10261033), only individuals in Florida had significantly higher levels than in the country as a whole. Dr. Wetmore’s group added that even in south Texas, “25(OH)D levels were relatively low and were no different than in the other areas examined.” The researchers acknowledged some important study limitations, including the retrospective nature of the study and the relatively small number of Caucasians, which the investigators noted was “a reality of our practice demography.” ■
10 Renal & Urology News
Pomegranate Extract Found to Increase PSADT MEN WITH RISING PSA following initial therapy for localized prostate cancer experienced an increase in PSA doubling time (PSADT) after being treated with pomegranate extract, according to a new study. In a phase 2 trial, researchers randomly assigned patients to receive either
1 or 3 grams of pomegranate extract daily for up to 18 months. For the 101 patients included in the analyses, the median PSADT increased from 11.9 months at baseline to 18.5 months after treatment. PSADT increased from 11.9 to 18.8 months in the low-dose group and from 12.2 to 17.5 months in the
high-dose group, with no significant difference between the treatment arms, researchers reported online in Prostate Cancer and Prostatic Diseases. The investigators, led by Michael A. Carducci, MD, of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University in Baltimore,
Brief Summary of Prescribing Information for: OMONTYS (peginesatide) Injection for intravenous or subcutaneous use WARNING: ESAs INCREASE THE RISK OF DEATH, MYOCARDIAL INFARCTION, STROKE, VENOUS THROMBOEMBOLISM, THROMBOSIS OF VASCULAR ACCESS AND TUMOR PROGRESSION OR RECURRENCE. See full prescribing information for complete boxed warning. Chronic Kidney Disease: • In controlled trials, patients experienced greater risks for death, serious adverse cardiovascular reactions, and stroke when administered erythropoiesis-stimulating agents (ESAs) to target a hemoglobin level of greater than 11 g/dL. • No trial has identified a hemoglobin target level, ESA dose, or dosing strategy that does not increase these risks [see Warnings and Precautions]. • Use the lowest OMONTYS dose sufficient to reduce the need for red blood cell (RBC) transfusions [see Warnings and Precautions]. INDICATIONS AND USAGE Anemia Due to Chronic Kidney Disease OMONTYS is indicated for the treatment of anemia due to chronic kidney disease (CKD) in adult patients on dialysis. Limitations of Use OMONTYS is not indicated and is not recommended for use: • In patients with CKD not on dialysis because of safety concerns in this population [see Warnings and Precautions]. • In patients receiving treatment for cancer and whose anemia is not due to CKD, because ESAs have shown harm in some settings and the benefit-risk factors for OMONTYS in this setting have not been evaluated [see Warnings and Precautions]. • As a substitute for RBC transfusions in patients who require immediate correction of anemia. • OMONTYS has not been shown to improve symptoms, physical functioning or health-related quality of life. CONTRAINDICATIONS OMONTYS is contraindicated in patients with: • Uncontrolled hypertension [see Warnings and Precautions]. WARNINGS AND PRECAUTIONS Increased Mortality, Myocardial Infarction, Stroke, and Thromboembolism • In controlled clinical trials of other ESAs in patients with CKD comparing higher hemoglobin targets (13 – 14 g/dL) to lower targets (9 - 11.3 g/dL) (see Table 2), increased risk of death, myocardial infarction, stroke, congestive heart failure, thrombosis of hemodialysis vascular access, and other thromboembolic events was observed in the higher target groups. • Using ESAs to target a hemoglobin level of greater than 11 g/dL increases the risk of serious adverse cardiovascular reactions and has not been shown to provide additional benefit. Use caution in patients with coexistent cardiovascular disease and stroke. Patients with CKD and an insufficient hemoglobin response to ESA therapy may be at even greater risk for cardiovascular reactions and mortality than other patients. A rate of hemoglobin rise of greater than 1 g/dL over 2 weeks may contribute to these risks. • In controlled clinical trials of ESAs in patients with cancer, increased risk for death and serious adverse cardiovascular reactions was observed. These adverse reactions included myocardial infarction and stroke. • In controlled clinical trials, ESAs increased the risk of death in patients undergoing coronary artery bypass graft surgery (CABG) and deep venous thrombosis (DVT) was observed in patients undergoing orthopedic procedures. The design and overall results of 3 large trials comparing higher and lower hemoglobin targets are shown in Table 2 (Normal Hematocrit Study (NHS), Correction of Hemoglobin Outcomes in Renal Insufficiency (CHOIR) and Trial to Reduce Cardiovascular Events with Aranesp® Therapy (TREAT)).
observed declining PSA levels in 13 patients (13%). Forty-two percent of patients left the study prematurely, mainly because of rising PSA levels. The researchers observed no significant changes in testosterone levels and no drug-related serious adverse events or deaths. ■
Table 2 Adverse Cardiovascular Outcomes in Randomized Controlled Trials Comparing Higher and Lower Hemoglobin Targets in Patients with CKD NHS (N = 1265) 1993 to 1996
CHOIR (N = 1432) Time Period of Trial 2003 to 2006 Patients with CKD Patients with CKD not on dialysis with on hemodialysis hemoglobin with coexisting CHF < 11 g/dL Population or CAD, hematocrit not previously 30 ± 3% on administered epoetin alfa epoetin alfa Hemoglobin Target; 14.0 vs. 10.0 13.5 vs. 11.3 Higher vs. Lower (g/dL) 12.6 (11.6, 13.3) 13.0 (12.2, 13.4) Median (Q1, Q3) vs. vs. Achieved Hemoglobin 10.3 (10.0, 10.7) 11.4 (11.1, 11.6) level (g/dL) Primary Endpoint
TREAT (N = 4038) 2004 to 2009 Patients with CKD not on dialysis with type II diabetes, hemoglobin ≤ 11 g/dL 13.0 vs. ≥ 9.0
12.5 (12.0, 12.8) vs. 10.6 (9.9, 11.3) All-cause mortality, All-cause mortality, All-cause mortality MI, myocardial MI, hospitalization or non-fatal MI ischemia, heart for CHF, or stroke failure, and stroke
Hazard Ratio or Relative Risk 1.28 (1.06 – 1.56) 1.34 (1.03 – 1.74) 1.05 (0.94 – 1.17) (95% CI) Adverse Outcome for All-cause mortality All-cause mortality Stroke Higher Target Group Hazard Ratio or 1.27 (1.04 – 1.54) 1.48 (0.97 – 2.27) 1.92 (1.38 – 2.68) Relative Risk (95% CI) Patients with Chronic Kidney Disease Not on Dialysis OMONTYS is not indicated and is not recommended for the treatment of anemia in patients with CKD who are not on dialysis. A higher percentage of patients (22%) who received OMONTYS experienced a composite cardiovascular safety endpoint event compared to 17% who received darbepoetin alfa in two randomized, active-controlled, open-label, multi-center trials of 983 patients with anemia due to CKD who were not on dialysis. The trials had a pre-specified, prospective analysis of a composite safety endpoint consisting of death, myocardial infarction, stroke, or serious adverse events of congestive heart failure, unstable angina or arrhythmia (hazard ratio 1.32, 95% CI: 0.97, 1.81). Increased Mortality and/or Increased Risk of Tumor Progression or Recurrence in Patients with Cancer receiving ESAs OMONTYS is not indicated and is not recommended for reduction of RBC transfusions in patients receiving treatment for cancer and whose anemia is not due to CKD because ESAs have shown harm in some settings and the benefit-risk factors for OMONTYS in this setting have not been evaluated. The safety and efficacy of OMONTYS have not been established for use in patients with anemia due to cancer chemotherapy. Results from clinical trials of ESAs in patients with anemia due to cancer therapy showed decreased locoregional control, progression-free survival and/or decreased overall survival. The findings were observed in clinical trials of other ESAs administered to patients with: breast cancer receiving chemotherapy, advanced head and neck cancer receiving radiation therapy, lymphoid malignancy, cervical cancer, non-small cell lung cancer, and with various malignancies who were not receiving chemotherapy or radiotherapy. Hypertension OMONTYS is contraindicated in patients with uncontrolled hypertension. Appropriately control hypertension prior to initiation of and during treatment with OMONTYS. Reduce or withhold OMONTYS if blood pressure becomes difficult to control. Advise patients of the importance of compliance with antihypertensive therapy and dietary restrictions. Lack or Loss of Response to OMONTYS For lack or loss of hemoglobin response to OMONTYS, initiate a search for causative factors (e.g., iron deficiency, infection, inflammation, bleeding). If typical causes of lack or loss of hemoglobin response are excluded, evaluate the patient for the presence of antibodies to peginesatide. In the absence of antibodies to peginesatide, follow dosing recommendations for management of patients with an insufficient hemoglobin response to OMONTYS therapy. Contact Affymax, Inc. (1-855-466-6689) to perform assays for binding and neutralizing antibodies. Dialysis Management Patients may require adjustments in their dialysis prescriptions after initiation of OMONTYS. Patients receiving OMONTYS may require increased anticoagulation with heparin to prevent clotting of the extracorporeal circuit during hemodialysis. Laboratory Monitoring Evaluate transferrin saturation and serum ferritin prior to and during OMONTYS treatment. Administer supplemental iron therapy when serum ferritin is less than 100 mcg/L or when serum transferrin saturation is less than 20%. The majority of patients with CKD will require supplemental iron during the course
Renal & Urology News 11
Vasculitis Patients’ Treatment Knowledge Lacking BY JILL STEIN PARIS—Patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis have substantial knowledge deficits about potential treatment-related adverse effects. Data from a British survey was completed by 378 patients who belong to
Vasculitis UK, a 700-member nationwide support group. The survey was developed by a multidisciplinary group involving nephrologists, rheumatologists, neurologists, otorhinolaryngologists, and opthalmologists and patient representatives. Mike Venning, MD, a consultant nephrologist at Manchester Royal Infirmary
of ESA therapy. Following initiation of therapy and after each dose adjustment, monitor hemoglobin every 2 weeks until the hemoglobin is stable and sufficient to minimize the need for RBC transfusion. Thereafter, hemoglobin should be monitored at least monthly provided hemoglobin levels remain stable. ADVERSE REACTIONS The following serious adverse reactions observed during clinical trials with OMONTYS are discussed in greater detail in other sections of the labeling: • Increased Mortality, Myocardial Infarction, Stroke, and Thromboembolism [see Warnings and Precautions] • Hypertension [see Warnings and Precautions] Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of OMONTYS cannot be directly compared to rates in the clinical trials of other drugs and may not reflect the rates observed in practice. Patients with Chronic Kidney Disease Adverse reactions were determined based on pooled data from two active controlled studies of 1066 dialysis patients treated with OMONTYS and 542 treated with epoetin, including 938 exposed for at least 6 months and 825 exposed for greater than one year to OMONTYS. The population for OMONTYS was 20 to 93 years of age, 58.5% male, and the percentages of Caucasian, Black (including African Americans), and Asian patients were 57.9%, 37.4%, and 3.1%, respectively. The median weight adjusted dose of OMONTYS was 0.07mg/kg and 113 U/week/kg of epoetin. Table 3 summarizes the most frequent adverse reactions (≥ 10%) in dialysis patients treated with OMONTYS. Table 3 Adverse Reactions Occurring in ≥10% of Dialysis Patients treated with OMONTYS Adverse Reactions
Dialysis Patients Treated with OMONTYS (N = 1066)
Gastrointestinal Disorders Diarrhea 18.4% Nausea 17.4% Vomiting 15.3% Respiratory, Thoracic and Mediastinal Disorders Dyspnea 18.4% Cough 15.9% Injury, Poisoning and Procedural Complications Arteriovenous Fistula 16.1% Site Complication Procedural Hypotension 10.9% Nervous System Disorders Headache 15.4% Musculoskeletal and Connective Tissue Disorders Muscle Spasms 15.3% Pain in Extremity 10.9% Back Pain 10.9% Arthralgia 10.7% Vascular Disorders Hypotension 14.2% Hypertension 13.2% General Disorders and Administration Site Conditions Pyrexia 12.2% Metabolism and Nutrition Disorders Hyperkalemia 11.4% Infections and Infestations Upper Respiratory Tract Infection 11.0%
Dialysis Patients Treated with Epoetin (N = 542) 15.9% 19.6% 13.3% 19.4% 16.6% 16.6% 12.5% 15.9% 17.2% 12.7% 11.3% 9.8% 14.6% 11.4%
and the University Hospital of South Manchester, presented the findings at the 49th Congress of the European Renal Association-European Dialysis and Transplant Association. Nina Brown, MD, a vasculitis research fellow at Manchester Royal Infirmary, was the principal investigator.
binding antibodies in patients dosed subcutaneously (1.9%) as compared to those dosed intravenously (0.7%). Peginesatide neutralizing antibodies were detected in vitro using a cell-based functional assay in 21 of these patients (0.9%). In approximately half of all antibody-positive patients, the presence of antibodies was associated with declining hemoglobin levels, the requirement for increased doses of OMONTYS to maintain hemoglobin levels, and/or transfusion for anemia of CKD. No cases of pure red cell aplasia (PRCA) developed in patients receiving OMONTYS during clinical trials. DRUG INTERACTIONS No formal drug/drug interaction studies have been performed. Peginesatide does not bind to serum albumin or lipoproteins as demonstrated in in vitro protein binding studies in rat, monkey and human sera. In vitro studies conducted with human hepatocytes or microsomes have shown no potential for peginesatide to induce or inhibit CYP450 enzymes. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C There are no adequate and well-controlled studies in pregnant women. Peginesatide was teratogenic and caused embryofetal lethality when administered to pregnant animals at doses and/or exposures that resulted in polycythemia. OMONTYS should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Administration of peginesatide by intravenous injection to rats and rabbits during organogenesis was associated with embryofetal toxicity and malformations. Dosing was every third day in rats for a total of 5 doses and every fifth day in rabbits for a total of 3 doses (0.01 to 50 mg/kg/dose). In rats and rabbits, adverse embryofetal effects included reduced fetal weight, increased resorption, embryofetal lethality, cleft palate (rats only), sternum anomalies, unossification of sternebrae and metatarsals, and reduced ossification of some bones. Embryofetal toxicity was evident in rats at peginesatide doses of ≥ 1 mg/kg and the malformations (cleft palate and sternoschisis, and variations in blood vessels) were mostly evident at doses of ≥ 10 mg/kg. The dose of 1 mg/kg results in exposures (AUC) comparable to those in humans after intravenous administration at a dose of 0.35 mg/kg in patients on dialysis. In a separate embryofetal developmental study in rats, reduced fetal weight and reduced ossification were seen at a lower dose of 0.25 mg/kg. Reduced fetal weight and delayed ossification in rabbits were observed at ≥ 0.5 mg/kg/dose of peginesatide. In a separate embryofetal developmental study in rabbits, adverse findings were observed at lower doses and included increased incidence of fused sternebrae at 0.25 mg/kg. The effects in rabbits were observed at doses lower (5% - 50%) than the dose of 0.35 mg/kg in patients. Nursing Mothers It is not known whether peginesatide is excreted in human milk. Because many drugs are excreted into human milk, caution should be exercised when OMONTYS is administered to a nursing woman. Pediatric Use The safety and efficacy of OMONTYS in pediatric patients have not been established. Geriatric Use Of the total number of dialysis patients in Phase 3 clinical studies of OMONTYS, 32.5% were age 65 and over, while 13% were age 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. OVERDOSAGE OMONTYS overdosage can elevate hemoglobin levels above the desired level, which should be managed with discontinuation or reduction of OMONTYS dosage and/or with phlebotomy, as clinically indicated. Cases of severe hypertension have been observed following overdose with ESAs [see Warnings and Precautions]. PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Medication Guide).
Marketed by: Affymax, Inc. Palo Alto, CA 94304
Distributed and Marketed by: Takeda Pharmaceuticals America, Inc. Deerfield, IL 60015
Seizures have occurred in patients participating in OMONTYS clinical studies. During the first several months following initiation of OMONTYS, blood pressure and the presence of premonitory neurologic symptoms should be monitored closely. Advise patients to contact their healthcare practitioner for new-onset seizures, premonitory symptoms, or change in seizure frequency. Allergic reactions have been reported in patients treated with OMONTYS. Discontinue OMONTYS and administer appropriate therapy if a serious allergic, anaphylactic or infusion-related reaction occurs. Immunogenicity Of the 2357 patients tested, 29 (1.2%) had detectable levels of peginesatidespecific binding antibodies. There was a higher incidence of peginesatide-specific
For more detailed information, see the full prescribing information for OMONTYS at www.omontys.com or contact Takeda Pharmaceuticals America, Inc. OMONTYS is a trademark of Affymax, Inc. registered in the U.S. Patent and Trademark Office and used under license by Takeda Pharmaceuticals America, Inc. All other trademarks are the property of their respective owners. ©2012 Takeda Pharmaceuticals America, Inc. March 2012 PEG096 R1
Despite advances in therapy, ANCAassociated vasculitis has a five-year mortality rate of 25% and is associated with major morbidities. The major causes of death are no longer active vasculitis but instead include cardiovascular disease, malignancy, and infection, all of which may be related to the use of immunosuppressive therapy. About 60% to 80% of patients with ANCA-associated vasculitis will have kidney involvement. The study aimed to assess patient knowledge of adverse effects with vasculitis therapy as well as uptake of screening and prophylactic measures to reduce these complications and adverse effects. Results revealed that 96% of patients had reportedly been treated with oral steroids, 75% with cyclophosphamide, and 69% with azathioprine. However, only 27% knew that potential side effects of such treatments included osteopenia/ osteoporosis. A similar percentage was aware of other steroid risks including poor healing and bruising.
A British survey reveals poor grasp of treatment-related adverse effects. While infection accounts for about half of all deaths during induction therapy over 12 months in newly diagnosed patients, only 10.5% of respondents were aware of their increased infection risk. Several studies have reported about a twofold increased cancer risk but only 16% of patients in this survey were aware of their heightened cancer risk. The study found variable results on uptake on prophylaxis or screening measures that may have been recommended by patients’ health care providers. The uptake of strategies to decrease steroid-related complications was generally good. Overall, 63% of patients had undergone bone scanning, and 59% had received calcium. Eighteen percent and 13% of patients, respectively, were aware of the need to limit sun exposure and monitor agents like azathioprine or cyclophosphamide due to a potential for increased malignancy risk. Dr. Venning, who is also the North of England Lead for the UK Vasculitis Registry and UK Vasculitis Rare Disease Working Group, said that the survey sample size was impressive given that vasculitis is a rare disease. ■
12 Renal & Urology News
On the Forefront
Urologists and nephrologists working together: an emerging model of patient care
Nephrectomy or Dialysis: Risk Stratification and Assessment BY SERGE GINZBURG, MD, AND ROBERT G. UZZO, MD, FACS
atients and physicians often make treatment tradeoff decisions based upon a complex series of subjective and imperfect assessments. One example is in patients with absolute or mandatory indications for nephron-sparing surgery (NSS). In such cases, the decision to either remove a kidney or to perform complex partial nephrectomy for presumed renal cell carcinoma (RCC) must be weighed against the functional implications of progressive CKD and potentially dialysis. At times, these decisions can mean a real tradeoff between two undesirable choices—assuming the risks of cancer or assuming those of dialysis.
Educating patients Educating and risk-stratifying such patients require a urologist’s understanding of the natural history of disease, competing risks, and morbidities of interventions, including minimally invasive ablative and extirpative approaches. Similarly, such decisions require insight into the natural history and tolerance of comorbid patients on hemodialysis. To decide between intervention and observation, we have operationalized point-of-care prediction tools using published predictive models and nomograms (www.cancermonograms.com). Given that the preponderance of data favor the use of NSS in most cases of T1 and even T2 RCC, we emphasize nephron-sparing interventions to maximize residual renal function.1, 2 Patients with already compromised renal function, or those with high risk of developing renal impairment after the intervention, are often referred to our nephrology colleagues for optimization and education on possible renal replacement options. A case study Such was the case with a 69-year-old male with two renal masses in a solitary right kidney found incidentally. Patient underwent contrast-based imaging as part of right-lower-quadrant pain
workup. Twenty years prior he underwent a radical nephrectomy on the contralateral side for a high grade, localized clear-cell RCC. Patient’s medical history included coronary artery disease managed with four-vessel coronary artery bypass grafting, insulin dependent diabetes, hypertension, peripheral vascular disease, CKD stage 3 (eGFR 53 mL/ min/1.73m2). The patient also suffered from alcoholism and had a 60 pack-year smoking history; although was highly functional with ECOG score 0. At the time of initial consultation he had interval computed tomography imaging five months apart which allowed us to characterize relative complexity and growth kinetics of the lesions. Both lesions were endophytic and of high complexity, yielding R.E.N.A.L. nephrometry scores of 2+3+3+a+3+h=11ah and 1+3+3+p+3=10p for the anterior and posterior interpolar lesions, respectively.3 (Figures 1a and 1b.) Due to concerning growth kinetics, his risk of death from presumed renal neoplasm was judged to be significant. Five year age-adjusted relative survival rate for such a patient on dialysis is reported to be 52%, outweighing the risks of nephron-sparing intervention and complications4.
Patient choice Desiring intervention and in an attempt to avoid renal replacement therapy, the patient opted for NSS in a form of retroperitoneal open partial nephrectomy. A ureteral stent was placed proactively to mitigate any potential urinary leak. Both lesions were resected with negative margins but a prolonged ischemic time (54 minutes). His postoperative course was complicated by prolonged acute tubular necrosis from surgical trauma and ischemia necessary to facilitate the resection (peak serum creatinine 2.71 mg/dL and eGFR 23 mL/min/1.73m2). Co-management by the nephrology team with fluid and electrolyte titration in perioperative and early postoperative settings were required. The patient was discharged home on postoperative day 8 but persisted with a small urine leak requiring continuous drainage to
Figure 1a. Anterior interpolar renal lesion
Figure 1b. Posterior interpolar renal lesion
bulb suction. Pathologic evaluation proved both lesions to be high grade clear cell RCC 4.5 cm (pT1bNxMo) and 1.8 cm (pT1aNxMo) for anterior and posterior interpolar masses, respectively. All margins of resection were negative. Ultimately, his renal function was preserved, with a threemonth post-operative eGFR of 46 mL/ min/1.73m2, avoiding renal replacement therapy. Serge Ginzburg, MD, is a urological oncology fellow and Robert G. Uzzo, MD, FACS, is Chief of Surgery at Fox
Chase Cancer Center in Philadelphia. Dr. Uzzo also is Medical Director for Urology at Renal & Urology News. REFERENCES 1. Campbell SC, Novick AC, Belldegrun A, et al. Guideline for management of the clinical T1 renal mass. J Urol 2009;182:1271-1279. 2. Long CJ, Canter DJ, Kutikov A, et al. Partial nephrectomy for renal masses ≥7 cm: technical, oncological and functional outcomes. BJU Int (published online ahead of print). 3. Kutikov A, Uzzo RG. The R.E.N.A.L. nephrometry score: a comprehensive standardized system for quantitating renal tumor size, location and depth. J Urol 2009;182:844-853. 4. Nordio M, Limido A, Maggiore U, et al. Survival in Patients Treated by Long-term Dialysis Compared With the General Population. Am J Kidney Dis 2012; 59(6):819-28
Stone Risk Raised by Calcium And Vitamin D Supplements Hypercalciuria and hypercalcemia linked to supplement use level below 20 ng/mL. Exclusion criteria were illness or medications known to affect vitamin D metabolism. The researchers defined hypercalcemia as a value greater than the normal range (8.910.3 mg/dL) and they defined hypercalciuria using a 24-hour urine calcium test that showed levels greater than normal
© PHOTO RESEARCHERS INC. / SOUTHERN ILLNOIS UNIVERSITY
BY JOHN SCHIESZER HOUSTON— Calcium and vitamin D supplements appear to be associated with higher calcium levels in the blood and urine, and this could increase the risk of kidney stones, according to a new study presented at The Endocrine Society’s 94th Annual Meeting.
Kidney stones may form as a result of high calcium levels in the blood and urine.
Not as benign as thought “The use of calcium and vitamin D supplementation may not be as benign as previously thought,” said principal investigator J. Christopher Gallagher, MD, Professor of Medicine and Director of the Bone Metabolism Unit at Creighton University Medical Center, Omaha, Neb. “Pending further information, people should not exceed the guidelines suggested by the Institute of Medicine, which are 800 IU of vitamin D, and 8001,200 mg per day of calcium.” Dr. Gallagher and his colleagues studied 163 healthy, postmenopausal women aged 52-85 years. The women were randomly assigned to receive either a vitamin D supplement of 400, 800, 1,600, 2,400, 3,200, 4,000, or 4,800 IU a day or placebo. In this study, the calcium intake was increased from an initial intake of 691 mg to 1,200-1,400 mg (average 1,280 mg) per day. The investigators measured blood and urinary calcium levels at the beginning of the study, and then every three months for one year. Inclusion criteria for this study were vitamin D insufficiency, defined as a serum 25-hydroxyvitamin D (25OHD)
(300 mg). Any abnormal event was verified after seven days; if the high values continued then the dose of the calcium supplements was reduced or vitamin D supplementation was stopped. The mean baseline serum 25OHD level was 15.6 ng/mL. The level increased on the highest dose of vitamin D to 45 ng/mL. Mean baseline serum calcium level was 9.47 mg/dL. This increased to 9.52 mg/dL. The mean 24-hour urine calcium level was 142 mg and increased to 186 mg, according to the researchers. The investigators found that 33% of subjects had an episode of hypercalciuria and approximately 10% had an episode of hypercalcemia on vitamin D and calcium. Altogether, the researchers observed 88 episodes of hypercalciuria and 25 episodes of hypercalcemia. The final 24-hour urine calcium increased slightly with vitamin D dose. However, no significant associations were found between episodes of hypercalciuria or hypercalcemia and vitamin D dose or serum 25 OHD. Prolonged hypercalciuria led to discontinuation of calcium in two subjects and discontinuation of calcium and vitamin D in three. No inci-
dents of kidney stones were reported during this 12-month study.
Monitoring important “Because of the unpredictable response, it is not clear whether it is the extra calcium, the vitamin D, or both together that cause these problems,” Dr. Gallagher said. “However, it is possible that long-term use of supplements causes hypercalciuria and hypercalcemia, and this can contribute to kidney stones. For these reasons, it is important to monitor blood and urine calcium levels in people who take these supplements on a long-term basis. This is rarely done in clinical practice.” Taking vitamin supplements has become a widespread practice throughout many parts of the world. In the United States alone, it is estimated that nearly two-thirds of women take vitamin supplements, with calcium and vitamin D among the most commonly used. Despite their popularity, the precise health effects of long-term calcium and vitamin D supplementation remain unclear. Previous research has indicated that hypercalciuria may increase the risk of kidney stones. Hypercalcemia has been associated with many complications, including bone and kidney problems.. In the Women’s Health Initiative study, researchers observed significant increases in renal stone incidents in women on a 400 IU a day dose of vitamin D3 and 1,000 mg extra calcium (total calcium intake 2,000 mg) after seven years. Hyper-absorbers Dr. Gallagher said he and his colleagues think the hypercalciuric and hypercalcemic events occur in women who are hyper-absorbers, “such as is seen in idiopathic stone formers. We expect that about 8% of the population has idiopathic hypercalciuria. So if 40 million women take calcium and vitamin D, then four million are at risk for hypercalciuria.” With respect to screening those at risk who should not take calcium supplements, he said their ROC analyses suggest that baseline 24-hour urine calcium should not exceed 180 mg. ■
Renal & Urology News 13
RP Suitable for High-Risk Localized PCa RADICAL PROSTATECTOMY (RP) for very high-risk locally advanced prostate cancer (PCa), with or without adjuvant or neoadjuvant treatment, can provide “very satisfactory” outcomes, according to researchers. The European Association of Urology and National Comprehensive Cancer Network guidelines accept RP as a treatment option in selected patients with locally advanced (cT3a) PCa. More controversy exists regarding the role of RP in very high-risk PCa—cancer that has invaded the seminal vesicles (cT3b) or has extended into the bladder neck (cT4). In a study of 51 patients with cT3b-T4 PCa who underwent RP, Steven Joniau, MD, of University Hospitals Leuven, Leuven, Belgium, and colleagues found that 10-year cancer-specific and overall survival rates were 91.9% and 70.7%, respectively. The 10-year rates of biochemical progression-free survival (BPFS) and clinical progression-free survival (CPFS)
Historically, locally advanced PCa had been considered inoperable. were 45.8% and 72.5%, respectively. Multivariate analyses showed that only pathologic stage was an independent predictor of BPFS and pathologic Gleason score and preoperative PSA levels were the only independent predictors of CPFS, Dr. Joniau’s group reported in the Scandinavian Journal of Urology and Nephrology (2012;46:164-171). Of the 51 patients, 17 (33%) received neoadjuvant androgen deprivation therapy (ADT) and 27 (52.9%) received adjuvant radiotherapy, adjuvant ADT, or both. Eighteen patients (35.3%) received salvage treatment.The researchers noted that locally advanced PCa had been considered inoperable historically, and has been treated mostly with ADT, radiotherapy, or both. The study population had a mean age of 64.2 years and a median follow-up of 108 months (range 11-210 months). Patients had a median preoperative PSA level of 16.9 ng/mL. In addition, 32 patients (62.7%) had positive surgical margins and 11 (21.6%) had positive lymph nodes. ■
14 Renal & Urology News
Sorafenib, Sunitinib Safe for the Heart Adjuvant use of either drug in patients with resected RCC did not increase the risk of cardiac events BY JOHN SCHIESZER CHICAGO—Sunitinib (SU) and sorafenib (SO) for adjuvant therapy will likely not cause significant cardiac toxicity in patients with resected renal cell carcinoma (RCC), according to a study presented at the American Society of Clinical Oncology 2012 annual meeting The study, by Naomi B. Haas, MD, Associate Professor of Medicine at the University of Pennsylvania in Philadelphia, Robert G. Uzzo, MD, FACS, Professor of Surgery at Temple University in Philadelphia, and colleagues, involved a cardiac analysis of 1,943 patients with resected high-risk RCC and normal left ventricular ejection fraction (LVEF). The study is a first “This study is the first to demonstrate that in the adjuvant setting these two drugs do not cause increased risk of cardiac events,” said Dr. Uzzo, Chief of Surgery at Fox Chase Cancer Center in Philadelphia. “This is the largest adjuvant kidney cancer trial ever done. It is also the first in the targeted therapy era.” Study patients had participated in E2805, a randomized, double-blind study in which patients were random-
1,293 patients had MUGA assessment at six months or later, including 397 in the SU arm, 394 in the SO arm, and 502 in the placebo group.
Robert G. Uzzo, MD, FACS
Naomi B. Haas, MD
ized to one of three treatment arms. Arm A included patients who received oral SU once daily for four weeks followed by rest for two weeks and oral placebo in place of SO twice daily for six weeks. Arm B included patients who received oral SO twice daily for six weeks and oral placebo in place of SU once daily for four weeks followed by rest for two weeks. Arm C included patients who received oral placebo in place of both drugs. Tumor tissue was collected prior to or during nephrectomy. Blood and urine samples were collected at baseline and periodically during study for biomarker correlative studies.
The objectives of the study were to determine if patients treated with sunitinib (SU) or sorafenib (SO) experienced clinically significant decreases in LVEF and to describe the frequency of clinically significant heart failure (HF). Dr. Haas’ group evaluated heart function using multiple gated acquisition (MUGA) scans at baseline and at three, six, and 12 months, and at the end of treatment. They also obtained MUGA scans if symptoms developed and at three months after the last abnormal assessment. Post-baseline MUGA scans were available for 1,589 of 1,943 patients;
Results The researchers defined the primary cardiac endpoint as an LVEF decline below the institutional lower limit of normal (ILN)—a 16% or greater decline from baseline occurring within six months of the start of therapy. The primary cardiac endpoint occurred in nine patients (2.3%) in the SU arm, seven (1.8%) in the SO arm, and five (1%) in the placebo arm. Clinically significant HF, which was defined as grade 3 or higher LV systolic or diastolic dysfunction, occurred in 11 patients: five SU recipients (1.2%), four SO recipients (1%), and two placebo recipients (0.4%). Eight patients had cardiac ischemia possibly or probably from treatment. Only one grade 4 event followed a primary LVEF event. The researchers concluded that cardiac function in patients starting with a normal EF was not impaired significantly with SU and SO compared with placebo. Ischemic events were uncommon and not clearly associated with treatment. ■
Axitinib May Work as First-Line Therapy for mRCC BY JOHN SCHIESZER CHICAGO—Axitinib appears to be effective in the first-line treatment of metastatic renal cell carcinoma (mRCC) as evidenced by a long progressionfree survival (PFS) and a high objective response rate, according to a new study presented at the American Society of Clinical Oncology 2012 annual meeting. Axitinib is a potent, selective, second-generation inhibitor of vascular endothelial growth factor receptors that has shown efficacy in mRCC. However, some patients have sub-optimal drug exposures at the standard 5 mg twice daily dose. Prior analyses indicated higher drug exposure enhanced efficacy and it is theorized that dose titration based on individual tolerability may optimize exposure and improve outcomes. Researchers conducted a randomized phase 2 trial that evaluated the efficacy and safety of axitinib
dose titration from 5 mg twice daily to a maximum of 10 mg twice daily in the first-line treatment of mRCC. “Up to 30% of patients may be under-dosed at the standard dose,” said lead investigator Brian I. Rini, MD, Associate Professor of Medicine
“We need to get smarter about how we dose this drug in our patients.” at Cleveland Clinic in Ohio. “The study shows that higher drug levels are associated with better outcomes.” In the study, patients with treatmentnaïve mRCC received axitinib 5 mg twice a day for a four-week lead-in period (cycle 1). Patients with two consecutive weeks of blood pressure (BP) measure-
ments of 150/90 mm Hg or less, no axitinib-related toxicities greater than grade 2, no dose reductions, and taking no more than two antihypertensive medications were then randomized in a double-blind fashion to axitinib 5 mg twice a day plus dose titration with either axitinib (arm A) or placebo (arm B). Patients ineligible for randomization continued with the same dose (arm C). The primary endpoint of the study was objective response rate (ORR). In all, 203 patients were accrued and 112 were randomized to arms A or B, and 91 to arm C. The mean age of the patients was 61 years (range 28-87 years) and 143 were male (67%). All patients had clear-cell histology and no prior systemic therapy for mRCC. In a blinded pooled analysis of data from arms A and B, the ORR was 43%; the ORR in arm C was 59%. The median progression-free survival (mPFS) was 14.5 months in arms A
and B combined and 16.4 months in arm C. Patients with drug exposure above the therapeutic threshold on day 15 of cycle 1 had longer mPFS and higher ORR than those with subtherapeutic exposure (mPFS 13.9 vs. 11 months). Patients with mean increases of diastolic BP of 15 mm Hg or higher as measured by ambulatory BP monitoring had a higher ORR than those with diastolic BP increases less than 15 mm Hg (60% vs. 51%). The most common adverse events were hypertension in 135 patients (63%), diarrhea in 123 (58%), and fatigue in 102 (48%). “It is a very effective drug for kidney cancer and we need to get smarter about how we dose this drug in our patients,” Dr. Rini told Renal & Urology News. “I think a significant number are being under dosed and it may be true for other oral agents for renal cell carcinoma.” ■
16 Renal & Urology News
The Urologist Who Became a Dean & QA
First, urologist Ralph V. Clayman, MD, wasn’t interested in leaving Washington University in St. Louis to become a
Chair until the opportunity arose in the newly formed urology department at the University of California-Irvine (UCI) School of Medicine. Then, he wasn’t interested in becoming UCI’s medical school dean. But 10 years later, Dr. Clayman continues to make his mark as one of only two urologists in the nation to become a medical school dean. He spoke candidly to Renal & Urology News senior editor Delicia Honen Yard about his experiences.
When did you first come to UCI School of Medicine? Dr. Clayman: In January 2002. Until then, urology was a division under the department of surgery, and I made it clear that I would not be able to come onboard unless it was a department. I’d been at Washington University for 17 years, and I was very happy there, and I had made a decision a long time ago that I would never, ever accept a chair unless urology was its own department.
Why was that a deal breaker? Dr. Clayman: As a division, you are part of another department. You do not have your own infrastructure, and you are beholding to the chair of that department, not to the dean of the school of medicine. But as a department, you have your own chief administrative and financial officers, and are more in control of your finances; also the person to whom you speak directly is the dean of the school of medicine. It elevates your discipline to a whole different stratum in the university.
So they made it a department in order for you to take on the role of chair. Did that rub some people the wrong way? Dr. Clayman: I don’t think that happened at all. First, when you become a department chair you often have a more favorable recruitment package and can hire more faculty and provide
additional resources to the faculty who are already at the institution. Second, in my case, Dr. Wilson, the Chair of Surgery, was very kind and supportive throughout the process.
How did you become dean of the medical school just seven years later? Dr. Clayman: We had a vice chancellor of health, who was responsible for both the school of medicine, in essence serving as dean, and, for the entire medical center; however, the hospital did have its own CEO in place who reported directly to the vice chancellor of health. In 2009, the vice chancellor stepped down and instead of recruiting for another vice chancellor, our leaders elected to change the model for the health enterprise to that of a dean of the school of medicine and a CEO of the hospital who would then work together and report directly to the Provost and the Chancellor of the university. An internal search for the dean was then initiated. I truly had no interest in the position and indeed when first asked to interview, I declined.
What were your priorities as interim, and then permanent, dean? Dr. Clayman: We had significant financial challenges and LCME [Liaison Committee on Medical Education] accreditation challenges. I knew that we’d have much to do to fulfill the
LCME requirements so that we were fully compliant. Within three years, thanks to tremendous efforts by our Senior Associate Dean of Education, Dr. Jerry Maguire, Nancy Koehring and the dedicated medical education staff, we are fully accredited and compliant in all areas. Also I was fortunate to come on as dean at the same time that a new CEO was hired, Mr. Terry Belmont. Together, we’ve been able to form a very strong partnership through which we have developed a campus-wide strategic plan that focuses on a care-oriented culture while being very supportive of research and education. Together we have also been able to achieve important financial milestones. Also, in 2009-2010 we opened a new hospital, new medical education building, and new research facility; these three events have transformed our campus.
Isn’t it unusual for a urologist to serve as dean of a medical school? Dr. Clayman: There is one other urologist dean in the country right now—Roger Hadley, at Loma Linda [California] University who has been dean there for more than a decade. It’s a bit unusual, quite honestly, for a surgeon to become a dean. However, I do believe there are certain parts of the
We have developed a strategic plan focused on a careoriented culture. —Ralph V. Clayman, MD
surgical mentality that can be of value in this role. As a group, surgeons tend to want to deal with a given problem in a definitive and expeditious manner; Also, above all else, the cornerstones of surgery are integrity and hard-work. People need to know that they can rely on you to be honest and, to be fair, to work hard in their best interest.
As the dean of the medical school, do you have any more plans for urology specifically? Dr. Clayman: When I assumed the role of interim dean, it was essential to me that Urology would be allowed to recruit a new chair from a national pool of applicants. We were fortunate enough to attract Dr. Jaime Landman from Columbia University [New York] to become the new Chair of Urology. He joined UC Irvine in January 2011, and has done a superb job. I am proud to be a member of his department and follow his plans for Urology, as I am still active clinically (albeit only 10% time).
As the dean of the medical school, what are your current priorities? Dr. Clayman: One of my top priorities is to hire proactive, renowned and accomplished chairs. I have been quite fortunate in that endeavor. When I began in March 2009, we had 11 interim chairs – today we have only one interim chair which we are hoping to fill before the year is out. Our mission is simple: Discover. Teach. Heal. In each of those realms we seek to be among the top 20 academic health centers in the country. Currently, we are in the top 50 and continuing to advance on the strength of our NIH funding, our unique digital tablet-based curriculum, and our world class patient care. Of note, we were the first medical school in the world to bring iPads into our classroom as an integral part of our educational process. The iPad was released in April 2010, and on August 8, 2010, all 104 of our first-year medical students received an iPad fully loaded with their curriculum and with all their books accessible electronically, thanks to a huge effort by Dr. Warren Wiechmann and his staff and to the visionary support of Mr. John Tu. In 2011 and again this year, all of our medical students will become part of our iPad iMedEd Initiative. ■
Renal & Urology News 17
Renal Nutrition Update THE CHRONIC Renal Insufficiency Cohort Study (CRIC) has recently shown potential benefits of vegetable protein intake in patients with mild-to-moderate CKD (J Ren Nutr 2012;22:379-388). The observational, cross-sectional study includes 2,938 participants with an estimated glomerular filtration rate (eGFR) ranging from 20-70 mL/min/1.73m2 in eight clinical centers.
Animal vs. plant protein A Diet History Questionnaire was administered to the participants at the first study visit to assess the percentage of animal versus plant protein consumed as well as other nutritional characteristics. The median protein intake was 0.7g/kg body weight/day with an interquartile range of 0.5-1.0 g/kg/day. The median percentage of total protein obtained from plant sources was 33%, with an interquartile range of 26%-42%. The investigators stratified the percent plant protein intake into quintiles. With respect to demographics, age and female gender were positively associated with increased intake of vegetable protein, whereas body mass index (BMI) was negatively associated. Increased percentage of calories from carbohydrate sources increased with higher plant protein intakes, while fat and protein calories decreased. Both total intakes and intakes adjusted for calorie consumption indicated lower intakes of sodium and phosphorus as plant protein increased, while potassium was only increased after adjusting for calorie intake. All three minerals showed decreased urinary concentrations with increasing plant protein consumption. Effects on FGF-23 With an adjusted model, the study found that fibroblast growth factor 23 (FGF-23) was significantly negatively associated with percentage plant protein intake and serum bicarbonate was significantly positively associated. This decrease in FGF-23 occurred even though serum phosphorus concentration did not significantly change related to vegetable protein intake. The reduced phosphorus intake and the fact that plant phosphorus compounds such as phytates are not easily absorbed in the
human gut may account for the effects on FGF-23. In addition, plant proteins contain reduced amounts of sulfur-containing amino acids. These amino acids markedly contribute to the acid load produced by protein. Thus, increased serum bicarbonate levels may be related to a decrease in sulfur amino acid load. These significant changes in FGF-23 and bicarbonate were seen in a population with a median vegetable protein intake of 33%. FGF-23 is a hormone produced in the bone that down regulates phosphorus reabsorption in the kidney and also down regulates the conversion of 25-hydroxyvitamin D to the active form. Thus, FGF-23 reduces serum phosphorus content by increasing excretion in the urine and decreasing absorption in the gut (Am J Kidney Dis 2012;59:135-144). Oral ingestion of phosphorus supplements can directly increase FGF-23 levels in healthy populations within five days. FGF-23 expression is increased by both vitamin D and PTH, whereas FGF-23 itself down regulates the expression of both hormones, indicating a negative feedback loop. Elevated plasma levels of FGF-23 have shown to be an independent risk factor for all-cause mortality in CKD and heart disease patients as well as a risk factor for progression to end-stage renal disease (ESRD) from CKD and to cardiovascular events in heart disease patients. These same results were not found in healthy populations. In relation to the CRIC study, the mean eGFR was 44, and 67% of participants had CKD stage 3. Although serum phosphate levels were no different between groups even though intake was significantly different as percentage plant protein intake increased, FGF-23 decreased significantly, suggesting that it is a more sensitive indicator of phosphorus balance in patients with mild-to-moderate CKD.
Contraindications The results from the CRIC study demonstrate possible benefits from increased plant protein intake. Because of the benefits of protein restrictions, typical recommendations support a focus on high
Plant protein intake may confer benefits in phosphorus and acid-base balance in mild-to-moderate CKD patients BY GRISSIM CLARK CONNERY, MS, RD, LD
Vegetable protein (soy-based above) can affect levels of FGF-23 and bicarbonate.
biological value protein sources, which primarily come from animal proteins. Plant foods also have increased amounts of potassium, and elevated potassium levels can be detrimental in the presence of renal insufficiency. In addition, the lower calorie and lower biological value of proteins associated with vegetable diets may put patients at risk of protein-energy wasting as kidney function declines further. Diets based on vegetable protein may confer some advantages. Because vegetable sources are not often as concentrated in protein as animal sources, patients may find it easier to be compliant with protein restrictions during mild-to-moderate CKD. Many meat products contain high
with a restricted protein diet may help prolong kidney function and reduce the time until ESRD. Furthermore, although potassium was significantly higher in relation to percentage of calories as plant protein intake increased, overall potassium intake was not significantly different between groups. In addition, urinary potassium excretion was lower with increased plant food intakes. This effect may account for the increase in bicarbonate levels since potassium is often bound with alkaline inducing anions such as citrate. Reducing sulfur-containing amino acids while holding potassium and alkaline anion intake constant may have resulted in the increase in bicarbonate. Potential benefits of veg-
Potential benefits of vegetable proteins may be more appropriate in prolonging decline in renal function in patients with lower CKD stages. amounts of sodium, saturated fat, and calories that can negatively impact blood pressure, blood lipids, and BMI. In the CRIC study, higher intake of vegetable proteins was associated with reduced intake of sodium, percent calories from fat, and BMI. In addition, higher plant protein intake was associated with increased bicarbonate levels. These factors in combination
etable proteins may be more appropriate in prolonging decline in renal function in patients with lower CKD stages who have less risk of protein-energy wasting and hyperkalemia. â– Mr. Connery is Research Coordinator at Case Western Reserve University in Cleveland.
18 Renal & Urology News
Diabetic Foot Ulcers Raise Death Risk BY JILL STEIN PHILADELPHIA—Diabetic patients on dialysis who have foot ulcers or who have undergone a foot amputation have a much higher mortality rate at two years than diabetic patients on dialysis without these pathologies, British investigators reported at the 72nd Scientific Sessions of the American Diabetes Association. Agbor Ndip, MD, specialist registrar and senior clinical fellow at the Manchester Royal Infirmary, and colleagues examined the impact of foot ulcers and amputations on mortality in 192 diabetic patients undergoing dialysis a their institution. Participants underwent comprehensive foot examination to assess for neuropathy, peripheral arterial disease, foot deformities, and foot ulcers/amputation. Overall, 102 patients (53.1%) had died after two years. Thirty-five (59.3%) of 59 patients who had a foot ulcer at baseline had died after two years compared with 55 (41.4%) of 133 patients who did not have a foot ulcer at baseline. Additionally, 26 (74.3%) of 35 patients who had a foot amputation at baseline were dead at two years versus 64 (40.8%) of 157 patients without amputation at baseline. The differences in two-year mortality rates between patients with and without foot pathology were statistically significant.Foot disease was a strong predictor
© ROBERTO A. PENNE-CASANOVA / PHOTO RESEARCHERS, INC.
Study reveals a 119% increased risk among diabetic dialysis patients
Active foot ulcers portend bad outcomes for diabetic dialysis patients.
of mortality on multivariate analysis that controlled for the type and duration of diabetes, age, gender, and patient history of retinopathy, ischemic heart disease, congestive heart failure, cerebrovascular disease, amputation, foot ulcer, peripheral vascular disease, and neuropathy, an active foot ulcer, or poor baseline glycemic control. Patients with an active foot ulcer had a 119% increase in the risk of death, whereas patients with a history of amputation had a 38% increased risk. “These data highlight the disquietingly high mortality rates in dialysis-treated
diabetic patients with foot ulcers or amputations and underscore the importance of integrating structured foot care and amputation prevention in dialysis units,” Dr. Ndip said. “On the positive side, dialysis patients frequently attend clinics [for dialysis] and are therefore amenable to preventive intervention.” Dr. Ndip acknowledged that it is not yet clear why dialysis patients with foot ulcers or amputations have a higher mortality rate than dialysis patients without such complications. “It may be that they are suicidal after having an amputation, as one audience member suggested,” he said. “However, the suggestion that the findings may be explained by the higher rate of comorbidities in dialysis patients is unfounded since our findings were maintained after we accounted for the classic risk factors for mortality.” He said that future research will involve an examination of patients’ death certificates or coroners’ reports to determine the cause of mortality. This study is the first of its kind to examine prospectively the effect of foot complications on mortality in dialysis patients, which allowed for good case ascertainment. However, Dr. Ndip added that only about 15% of patients had foot amputations at the time of enrollment, which may be a potential study limitation. ■
High Uric Acid Raises CKD Risk PARIS—High levels of uric acid are associated with an increased risk of chronic kidney disease (CKD), especially among hypertensive individuals, according to data presented at the 49th Congress of the European Renal Association-European Dialysis and Transplant Association. Investigators at Erasmus Medical Center in Rotterdam, The Netherlands, studied 5,139 individuals aged 55 years and older. Each 1 mg/dL increment in serum uric acid level was associated with a 0.22 mL/min/ 1.73 m2 increase in estimated glomerular filtration rate (eGFR) decline and a 34% increase in the incidence of CKD. The researchers reported that the association was significantly stronger in hypertensive compared with normotensive individuals. When the investigators combined their findings with those of other studies in a meta-analysis, they found that each 1 mg/dL increment in uric acid was associated with a 15% increased risk for CKD. Adequate monitoring and management of abnormal serum uric acid levels appears to be important in preventing development of CKD in hypertensive individuals. The investi-
Decision Tool Helps Cuts RRT Referral Time
gators used the Modification of Diet in Renal Disease (MDRD) study equation to calculate eGFR and defined CKD as
BY JILL STEIN PARIS—Primary care physicians who use a clinical decision support system (CDSS) may be able to avoid late referrals for renal replacement therapy (RRT), researchers reported at the 49th Congress of the European Renal Association-European Dialysis and Transplant Association. Christopher Farmer, MD, a renal consultant at East Kent University Hospitals NHS Foundation in Kent, UK, and colleagues tested the impact of a CDSS on the incidence of late referral to their renal service. “Timely referral is requisite for ensuring favorable outcomes in patients reaching end-stage renal failure,” Dr. Farmer said. “We know that patients who are referred late are about twice as likely to die within 90 days of starting dialysis, they are more likely to be denied the possibility of choosing
their treatment, and they are much less likely to start peritoneal dialysis, and so they tend to start on hemodialysis. And, finally, there is no possibility for preemptive transplantation, which is clearly the best treatment for end-stage kidney disease. So, in short, you are limiting the patient’s choice.” The investigators developed a CDSS that is an algorithm available as computer software that screens patients having serum creatinine estimates in primary care. Data are routinely extracted from primary care databases and patientspecific advice is given to primary care physicians about referrals, medical management of co-morbidities such as hypertension and diabetes, and additional investigations that might be needed to screen patients for anemia or disorders of calcium and phosphate. Over a recent four-year period, Dr. Farmer’s team tested the tool in
patients for whom estimated serum creatinine levels were available. “What we found was significantly fewer ‘crash landers’ when physicians used the system,” Dr. Farmer said. “By ‘crash landing,’ I am referring to patients who were referred less than 90 days before starting RRT.” The “crash lander” rate in patients from primary care practices that did not use the CDSS was 25% versus 6% in patients from practices that had used the CDSS. “The difference between the two groups was huge and significant,” Dr. Farmer said. He cautioned that the primary care practices included in the analysis were not randomly selected. “There may be selection bias in that practices that are better. They may be more innovative and may be more likely to opt to participate in a managed care program that uses a CDSS system or the like,” he said. ■
a decline in eGFR to below 60. The study is not the first to link higher serum uric acid levels to an increased risk of CKD. In a 10.2-year prospective cohort study involving 14,939 individuals aged 20-84 years who completed medical questionnaires and medical examinations, Yejin Mok, MD, and colleagues at Yonsei University in Seoul, Korea, found that men and women in the highest quartile of serum uric acid had a 2.1 times and 1.3 times increased risk of CKD, respectively, compared with their counterparts in the lowest quartile, after controlling for age, life style and cardiovascular risk factors, according to a report published online ahead of print in Nephrology Dialysis Transplantation. ■
20 Renal & Urology News
Practice Management For nephrologists and urologists, the transition to ICD-10 will not be as bad as for some other specialists BY TAMMY WORTH
Possible delay The original date for the transition to ICD-10 was set for October 1, 2013, but the Department of Health and Human Services in April announced a proposed rule that would extend
“We don’t know when it will be—it could be months or a year,” she said. “We are in a waiting game right now, so one of the things that we have been telling everyone is that if you have begun preparing, you shouldn’t stop.”
Preparation According to CMS, this process can be broken down into the following stages: Planning. CMS recommends creating a project management structure, a plan to communicate with vendors and other partners and understanding risk management. Communicating with staff. Physicians will need to assess what kind of training is required and develop a training plan. Then they will have to meet with staff to discuss their new responsibilities. Assessment. Aside from the new staff impact, providers will need to understand how the change will affect their business policy, operations, technology, vendors, and so forth. Implementation. This includes system migration strategies, business and technical changes, and training. AAPC recommends waiting until late 2012 to begin training so staff will retain the information. Additionally, there is internal and external testing and the transition to the live environment, which
Where ICD-9 would have had two or three codes for a patient with diabetes and renal failure, there will be only one in ICD-10. the deadline to October 1, 2014. This should not halt the switching process if providers are already working on the transition, said Rhonda Buckholtz, vice president of ICD-10 training and education at AAPC (formally the American Academy of Professional Coders), a credentialing and certification organization.
includes ongoing support. CMS has made available on its website (www.cms.gov/ ICD10) implementation guides for small, medium, and large practices as well as payers and small hospitals.
Cost One consideration for switching over is cost. According to a report
he move from ICD-9-CM to ICD-10 is enough to strike fear into the hearts of physicians and staff alike. Making the leap from 14,000 codes to almost 69,000, topped with the huge cost to make that change, is understandably daunting. The more you know, the better off your practice will be. Following is some information about the new system and tips for preparation. ICD-10 is a diagnostic classification that has been used since 1994 by many World Health Organization Member states. Aside from being a way in which insurance companies determine billing, it is used for health management and epidemiologic purposes. The Centers for Medicare & Medicaid Services (CMS) says the move to ICD10 is being made because its predecessor is outdated, lacks specificity, and does not provide enough details regarding health data (such as disease severity and complexity), thus making it difficult to reimburse accurately.
Physicians will need to meet with staff to discuss their new responsibilities.
by the Medical Group Management Association, small practices can expect to spend about $83,000; medium groups will spend $285,000; and large practices can expect to spend $2.7 million to comply with the mandate. The cost will come from six areas: education and training for the staff; analysis of insurance contracts and documentation; superbill changes; IT changes; documentation costs; and cash flow disruption.
Vendors Buckholtz has seen with both the Health Insurance Portability and Privacy Act (HIPAA) and Version 5010 that some vendors waited until the last minute and told providers they weren’t ready. Don’t let this happen to you. Both hardware and software have to be compatible with the new system. Because ICD-9 may still be around for some time (some entities like worker’s compensation are not required under HIPAA to switch), a system needs
to have the capacity to accommodate both codes. Other than compatibility, accommodation for both systems, cost, and system availability, providers should ensure that their vendor will also be available for testing, implementation, training, and customer support.
The good news The transition for nephrologists and urologists will not be as bad as for some other specialists, Buckholtz said. “Their codes are straightforward and they will run into new combination codes for those with comorbidities like diabetes,” she said. “Once they get accustomed to those codes, the rest are pretty straightforward.” Where ICD-9 would have had two or three codes for a patient with diabetes and renal failure, there will be only one in ICD-10. ■ Tammy Worth is a freelance medical journalist based out of Blue Springs, MO.
Tool Helps Educate Diabetic Latinos about CVD Risks Multimedia Spanish-language program prompts therapeutic intervention English-speaking population and believed it would be well-suited to the local Latino population. “A lot of area physicians aren’t fluent in Spanish, and a lot of our Hispanic immigrants have low literacy not only in English but also in their native Spanish, and we felt that
BY JILL STEIN PHILADELPHIA—Investigators believe a multimedia Spanish-language program intended to teach high-risk Latinos with diabetes about cardiovascular disease (CVD) has major potential.
Patients view a set of video presentations on a tablet computer just before a clinic visit.
Preliminary results released at the 72nd Scientific Sessions of the American Diabetes Association show that the program stimulated therapeutic interventions related to CVD risk. In fact, patients who were taught about CVD using the multimedia program just prior to visits with their primary care physicians were more likely to discuss their CVD risk during their visits or to have a change in medication directed toward CVD risk factors than patients undergoing usual care.
Risk factors undertreated “Cardiovascular disease is the major cause of mortality in Latinos with type 2 diabetes yet CVD risk factors are undertreated in this population,” said Paris Roach, MD, Associate Professor of Clinical Medicine at Indiana University School of Medicine in Indianapolis. “In the Indianapolis area, we have a large Spanish-speaking population of primarily Mexican immigrants with type 2 diabetes.” His team had found that the multimedia program is effective in an
the program with its audiovisuals and simple explanations would be a natural fit for this population.” Dr. Roach and colleagues randomized four urban primary care clinics to the intervention (70 patients) or usual care (52 patients). Study participants had type 2 diabetes without CVD but had at least one uncontrolled CVD risk factor. Their low-density lipoprotein (LDL)–cholesterol level was greater than 130 mg/dL, their systolic blood pressure (SBP) was greater than 150 mm Hg, or their hemoglobin A1C was higher than 8.0%.
Patients informed of CVD risk The multimedia program consists of a series of video presentations that patients view on a tablet computer immediately before their outpatient clinic visits. Each presentation incorporates individualized CVD risk factor data and the patient’s 10-year CVD risk based on U.K. Prospective Diabetes Study (UKPDS) Risk Engine estimates. The UKPDS is a landmark randomized, controlled trial which showed that
both intensive treatment of blood glucose and blood pressure can lower the risk of diabetes-related complications in individuals newly diagnosed with type 2 diabetes. Patients who participate in the multimedia program also receive a one-page printout showing their updated CVD risk factor risk factor status for use during consultation with the health care provider. “We wanted to be able to effectively communicate CVD risk in our target population, and this means putting the risk message into a context that patients can understand,” Dr. Roach said. “Often patients hear this ‘alphabet soup’ of LDL-cholesterol, A1c, and so on, and they also hear about heart attacks, and strokes, but they never completely grasp the meaning of these outcomes in terms of overall health risk. Specifically, we tell the patient his/her risk of a heart attack over the next 10 years compared to a non-diabetic age- and sex-matched individual, and we explain to them how to lessen that risk.” The primary endpoint was the rate of therapeutic intervention per 12 months of follow-up, defined as a discussion of CVD risk with their physician during their visits based on exit interviews or a change in medications directed at a CVD risk factor based on medical chart review. The study found that the rate of therapeutic intervention was 87% higher in the group assigned to the multimedia program compared with usual care (19.6 vs. 10.5 interventions per patient per 12 months). Additionally, 94% to 100% of exit survey responses from patients in the intervention group indicated that the program facilitated interactions with their physicians. “We now have evidence that this risk communication tool stimulates the patient and physician to discuss CVD risk and to intensify therapy,” Dr. Roach noted, adding that the next step is adapting the program for use in the real world. Dr. Roach’s work was supported by a grant from the Robert Wood Johnson Foundation’s Finding Answers: Disparities Research for Change program. ■
Renal & Urology News 21
NSAIDs Raise Risk of PCa, Study Finds BANFF, Alberta—Use of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with an increased likelihood of having prostate cancer (PCa) found on prostate biopsy, according to data presented at the Canadian Urological Association annual meeting. Bimal Bhindi, MD, and colleagues at the University of Toronto studied 931 men undergoing prostate biopsy. Patients taking aspirin and other NSAIDs had a significantly higher rate of biopsy-detected PCa than those taking no NSAIDs (65% vs. 42%). After adjusting for multiple variables, use of aspirin and other NSAIDs was associated with a significant twofold and threefold higher odds of PCa detection, respectively, compared with no NSAID use. Additionally, use of aspirin, but not other NSAIDs, was associated with a significant 64% increased odds of having high-grade PCa detected compared with no NSAID use.
High-grade disease linked to the use of aspirin, not other NSAIDS. These findings contrast with those of most epidemiologic studies in the published literature, the researchers noted. The investigators pointed out, however, that aspirin and other NSAIDs still may have chemopreventive effects because patients whose cancers were prevented would not have been referred for biopsy. At the European Association of Urology 27th Annual Congress in Paris earlier this year, Finnish researchers reported on a study showing that NSAID use is associated with a 31% increased risk of PCa overall and a 63% increased risk of advanced PCa, after adjusting for potential confounders. However, a study published in the June issue of the British Journal of Cancer (2012;107:207-214) found that daily aspirin use was associated with lower PCa risk. The effect of taking at least one aspirin daily was more pronounced when analyses were restricting men older than 65 years or men with a history of cardiovascularrelated diseases or arthritis. ■
22 Renal & Urology News
Earlier Abiraterone Use Shows Promise The drug was used with leuprolide for high-risk localized prostate cancer in a phase 2 study BY JOHN SCHIESZER CHICAGO—A six-month course of the targeted therapy for prostate cancer (PCa) with abiraterone acetate, in addition to standard hormonal therapy before surgical prostatectomy, may help eliminate or nearly eliminate cancer in some men with localized high-risk PCa, according to a randomized phase 2 study presented at the American Society of Clinical Oncology 2012 annual meeting. The study marks the first time abiraterone (a drug that is FDA approved for treating advanced PCa) has been explored for the treatment of earlier stages of PCa, including in the neoadjuvant setting. “For this proportion of patients with high-risk disease to have very little to no detectable cancer in the prostate after six months of therapy is dramatic,” said lead researcher Mary-Ellen Taplin, MD, Associate Professor of Medicine at Harvard Medical School and a medical oncologist at DanaFarber Cancer Institute in Boston. “Our findings suggest that this combination
therapy approach could improve outcomes for a substantial number of men, but larger, long-term trials are needed to confirm this approach.” Localized high-risk disease is defined as prostate cancer in men with a PSA level above 20, high-grade disease (a Gleason score of 8 or more), or stage T3 disease. Previous studies have shown that use of standard hormonal therapy alone, including treatment with leuprolide, before surgery had limited benefits for men with localized highrisk PCa. In the current study, Dr. Taplin and her colleagues evaluated the effect of adding abiraterone to leuprolide in two groups of men with localized high-risk disease: Group A included 27 men who received leuprolide hormonal therapy for 12 weeks followed by leuprolide plus abiraterone for another 12 weeks. The second group (Group B) included 29 men who received both abiraterone and leuprolide for the entire 24-week period. Prostate surgery was performed in all men after 24 weeks of
therapy, and the tissue was examined for evidence of cancer. Among men in Group B (24 weeks of abiraterone therapy), 34% had either complete elimination (three patients) or nearly complete elimination (seven patients) of their cancer upon surgery. In Group A (12 weeks of abiraterone
Combined therapy eliminated or nearly eliminated PCa in some patients. therapy), 15% of men had either complete elimination (one patient) or nearly complete elimination (three patients) of their cancer upon surgery. Therapy was well-tolerated by both groups. “Very high-risk cancers localized to the prostate are rarely cured by prostatectomy alone,” Dr. Taplin said. “Therapies that combine surgery with older androgeninhibiting drugs have not historically improved outcomes. This unmet need
has given rise to efforts to develop new drugs capable of more completely reducing androgen levels within the tumors.” Conventional therapies target androgen production in the testes and adrenal glands, but not within the tumor itself. Abiraterone is capable of blocking androgen production in all three sites. The clinical benefit of intensive androgen deprivation therapy, either before or after prostatectomy, will need to be validated in prospective, randomized clinical trials, but these data suggest a benefit for some men. E. David Crawford, MD, Professor of Surgery/Urology/Radiation Oncology at the University of Colorado in Denver, said the new study is a very important and could affect clinical practice if the findings are confirmed. “This is an exciting study, which is moving one of our very powerful drugs up in therapy,” Dr. Crawford said. “With all the concerns about over diagnosis and treatment, this study focuses where we need to make an impact. However this is a small study and further ones will be needed.” ■
Axitinib May Offer Advantage Over Sorafenib for mRCC BY JOHN SCHIESZER CHICAGO—Axitinib provides better outcomes than sorafenib as second-line treatment for patients with metastatic renal cell carcinoma (mRCC) previously treated with cytokines, according to a new study. In a phase 3 trial, patients who received axitinib experienced a near doubling of median progression-free survival (PFS) compared with those who received sorafenib, investigators reported at the American Society of Clinical Oncology annual meeting. “The take-home message is that axitinib is a second-generation TKI [tyrosine kinase inhibitor] that is very active in the treatment of metastatic renal cell carcinoma and should be strongly considered as a second-line standard of care for patients with advanced renal cancer,” said study investigator M. Dror Michaelson, MD, Assistant Professor of Medicine at Massachusetts General Hospital Cancer Center in Boston. “It has impressive efficacy and it generally very well tolerated by the patients.”
He noted that this study was the first reported phase 3 trial to compare two TKIs head to head in renal cancer. Dr. Michaelson and his colleagues presented findings of a subset analysis of mRCC patients who received cytokines as first-line therapy. The researchers enrolled 723 patients with clear-cell mRCC and progressive disease after one systemic therapy. Among these patients, 251 received prior interleukin-2 (IL-2)
In a phase 3 trial, patients who received axitinib had better survival rates. or interferon-α (IFN-α). Patients were randomized to receive axitinib (5 mg twice daily starting dose) or sorafenib (400 mg twice daily). The mean age of the patients in the axitinib group was 61 years (range 20-82 years) and 75% were male. The mean age of the patients in the sorafenib group was 60
years (range 35-79 years) and 69% were male. The median PFS for cytokinetreated patients was 12.0 months (range 10.1-13.9) with axitinib versus 6.6 months (range 6.4-8.3 months) with sorafenib. For those treated with an IL-2-containing regimen, the median PFS was 15.7 months (range 8.3-19.4) with axitinib versus 8.3 months (range 4.7-15.7 months) with sorafenib. For those treated with IFN-α, the median PFS was 12.0 months (range 10.0 -13.8) with axitinib versus 6.5 months (range 6.4-8.2) with sorafenib. As of November 1, 2011, the median overall survival in the cytokine-treated subgroup was 29.4 months with axitinib compared with 27.8 months with sorafenib. Dr. Michaelson further noted that “the overall survival in both arms compares favorably with historical results, and likely reflects general improvement in care and encouraging therapeutic advances for RCC patients over the past decade.” With respect to adverse events, fatigue, dysphonia, and hypothyroidism were more common with axitinib, whereas
M. Dror Michaelson, MD
hand-foot syndrome, alopecia, and rash were more common with sorafenib. In all, seven patients (5.6%) previously treated with cytokines discontinued axitinib and nine (7.3%) discontinued sorafenib due to toxicity. Of patients previously treated with cytokines who discontinued treatment with axitinib or sorafenib, 46% in each arm received follow-up systemic therapy. ■
24 Renal & Urology News
Your Money Fundamental index funds weigh holdings according to revenue stream and dividends, and can offer attractive payouts BY STAN LUXENBERG
Fundamental index funds Now, a challenger to Bogle’s invention has appeared. Known as fundamental index funds, the new breed aims to outdo the S&P 500 and other traditional benchmarks. Lately, many fundamental funds have been achieving their goals. A top performer is PowerShares FTSE RAFI
ally for the past three years, topping the benchmark by eight percentage points.
Structuring portfolios Proponents of the fundamental approach claim that it excels because of flaws in the way that traditional funds structure their portfolios. Traditional S&P 500 funds invest in the stocks of 500 companies. Each holding is weighted according to the market value of the stock. One of the biggest stocks in the S&P is Exxon Mobil. The total value of all the oil giant’s shares is $404 billion. Based on that figure, the company’s shares account for 3.4% of the assets in the S&P 500. So, if you put $100 into an S&P fund, $3.40 will go into stock of the oil company. As a stock appreciates, it’s weighting in the S&P 500 can rise, while the weighting of unloved shares can decline. The flaws in the system became clear during the bull market of the late 1990s when a handful of big technology stocks soared. As shares of Microsoft and Dell appreciated, they came to account for a big percentage of assets in the S&P 500. As a result, investors who put cash into an index fund were keeping more of their assets in expensive technology stocks. When the technology stars collapsed in 2000, the index funds sank hard. The S&P 500 trailed funds that did not put so much weight on a few high-priced stocks.
In fundamental funds, bonds are weighed according to a variety of factors, including the sales and profits of an issuer. 1000, a fundamental fund that holds large stocks. During the past three years, the fund has returned 25.1% annually, surpassing the S&P 500 by six percentage points, according to fund tracker Morningstar. Another winning fund is Schwab Fundamental US Small/Mid Company, which returned 31.4% annu-
To avoid emphasizing expensive stocks, fundamental funds weigh holdings according to financial measures such as a company’s revenue, dividends, or earnings. According to advocates of fundamental benchmarks, indicators such as revenues can provide a consistent picture of a stock’s value that is not distorted by
© PHOTO CREDIT
n 1976, Vanguard Group introduced a new kind of mutual fund, an index fund designed for retail investors. Vanguard Index 500 Fund sought to deliver the same returns as the S&P 500 benchmark. The idea was revolutionary. Until then, fund portfolio managers aimed to outperform the benchmarks by actively picking the best stocks and bonds. But Vanguard founder John Bogle argued that most active portfolios failed to match the benchmarks. The active funds often produced disappointing results because managers picked the wrong stocks or imposed excessive fees that dragged down returns. Most investors would get better results by simply matching the market average, Bogle said. Over the years, Bogle’s idea became widely popular. While some index funds track the S&P 500, others mimic the performance of benchmarks that include bonds or foreign issues. Today, index funds account for about 20% of the $11.8 trillion in mutual funds.
Fundamental funds do not put a big emphasis on a handful of expensive stocks.
temporary swings in market moods. As a result, fundamental funds do not put a big emphasis on a handful of expensive stocks. Consider RevenueShares Large Cap, a fundamental fund that puts the most weight on companies with the greatest sales. The fund has 1.1% of its assets in Apple. In contrast, the S&P 500 has 3.4% of its assets in Apple, a company with a highflying stock price. Some of the most intriguing fundamental funds focus on dividends. A solid choice is WisdomTree Emerging Markets SmallCap Dividend, which has returned 33.5% annually during the past three years and outdid its average competitor by seven percentage points. WisdomTree holds about 500 dividend-paying stocks. The companies that pay the most total dividends receive the greatest weight in the portfolio. WisdomTree offers investors a dividend yield of 3.7%. That is an attractive payout at a time when the stocks of the S&P 500 yield 2.0%, and moneymarket funds pay next to nothing. Fundamental funds also offer a promising way to hold bonds. An intriguing choice is PowerShares Fundamental High Yield Corporate Bond Fund, which yields 5.6%. The fund weighs bonds according to a variety of factors, including the sales and profits of an issuer. Under the funda-
mental system, companies with more sales and profits have heavier weightings than issues with small sales and scant profits. In contrast, traditional bond index funds weight bonds according to the amount of debt that issuers have. So, a struggling borrower with huge amounts of debt will have a bigger weighting than a competitor with little debt.
Traditional bond index funds To appreciate the problem of traditional bond index funds, consider Fidelity Spartan U.S. Bond Index, a fund that tracks the Barclays Capital U.S. Aggregate Bond Index, a popular benchmark. The traditional Barclays index includes a mix of government and corporate bonds. But in recent years, the biggest issuer by far has been Uncle Sam. Struggling to finance mounting expenditures, the government has sold a flood of bonds. As Washington has become more indebted, its bonds have come to account for a bigger percentage of the benchmark. Now Treasuries account for 35% of the Barclays benchmark, up from 21% in 2002. In recent years, Treasury bonds have held their value. But at some point, their prices could fall. That could punish conventional bond index funds and persuade investors to try the fundamental funds. ■
28 Renal & Urology News
Prophylactic Sling May Lower Incontinence Risk PLACEMENT OF a midurethral sling during vaginal surgery for pelvic-organ prolapse decreases the likelihood of postoperative urinary incontinence, but it also is associated with higher rates of adverse events, a study found. Investigators randomly assigned 337 women undergoing surgery for anterior Brief Summary: Consult package insert for complete Prescribing Information INDICATIONS AND USAGE: Bone Metastasis from Solid Tumors. Xgeva is indicated for the prevention of skeletal-related events in patients with bone metastases from solid tumors. Important Limitation of Use. Xgeva is not indicated for the prevention of skeletal-related events in patients with multiple myeloma (see Clinical Trials  in Full Prescribing Information). DOSAGE AND ADMINISTRATION: Recommended Dosage. The recommended dose of Xgeva is 120 mg administered as a subcutaneous injection every 4 weeks in the upper arm, upper thigh, or abdomen. Administer calcium and vitamin D as necessary to treat or prevent hypocalcemia (see Warnings and Precautions). Preparation and Administration. Visually inspect Xgeva for particulate matter and discoloration prior to administration. Xgeva is a clear, colorless to pale yellow solution that may contain trace amounts of translucent to white proteinaceous particles. Do not use if the solution is discolored or cloudy or if the solution contains many particles or foreign particulate matter. Prior to administration, Xgeva may be removed from the refrigerator and brought to room temperature (up to 25Â°C/77Â°F) by standing in the original container. This generally takes 15 to 30 minutes. Do not warm Xgeva in any other way (see How Supplied/Storage and Handling). Use a 27-gauge needle to withdraw and inject the entire contents of the vial. Do not re-enter the vial. Discard vial after single-use or entry. HOW SUPPLIED/STORAGE AND HANDLING: Xgeva is supplied in a single-use vial. Store Xgeva in a refrigerator at 2Â°C to 8Â°C (36Â°F to 46Â°F) in the original carton. Do not freeze. Once removed from the refrigerator, Xgeva must not be exposed to temperatures above 25Â°C/77Â°F or direct light and must be used within 14 days. Discard Xgeva if not used within the 14 days. Do not use Xgeva after the expiry date printed on the label. Protect Xgeva from direct light and heat. Avoid vigorous shaking of Xgeva. CONTRAINDICATIONS: None. WARNINGS AND PRECAUTIONS: Hypocalcemia. Xgeva can cause severe hypocalcemia. Correct pre-existing hypocalcemia prior to Xgeva treatment. Monitor calcium levels and administer calcium, magnesium, and vitamin D as necessary. Monitor levels more frequently when Xgeva is administered with other drugs that can also lower calcium levels. Advise patients to contact a healthcare professional for symptoms of hypocalcemia (see Adverse Reactions and Patient Counseling Information  in full Prescribing Information). Based on clinical trials using a lower dose of denosumab, patients with a creatinine clearance less than 30 mL/min or receiving dialysis are at greater risk of severe hypocalcemia compared to patients with normal renal function. In a trial of 55 patients, without cancer and with varying degrees of renal impairment, who received a single dose of 60 mg denosumab, 8 of 17 patients with a creatinine clearance less than 30 mL/ min or receiving dialysis experienced corrected serum calcium levels less than 8.0 mg/dL as compared to 0 of 12 patients with normal renal function. The risk of hypocalcemia at the recommended dosing schedule of 120 mg every 4 weeks has not been evaluated in patients with a creatinine clearance less than 30 mL/min or receiving dialysis. Osteonecrosis of the Jaw (ONJ). Osteonecrosis of the jaw (ONJ) can occur in patients receiving Xgeva, manifesting as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration, or gingival erosion. Persistent pain or slow healing of the mouth or jaw after dental surgery may also be manifestations of ONJ. In clinical trials, 2.2% of patients receiving Xgeva developed ONJ; of these patients, 79% had a history of tooth extraction, poor oral hygiene, or use of a dental appliance (see Adverse Reactions). Perform an oral examination and appropriate preventive dentistry prior to the initiation of Xgeva and periodically during Xgeva therapy. Advise patients regarding oral hygiene practices. Avoid invasive dental procedures during treatment with Xgeva. Patients who are suspected of having or who develop ONJ while on Xgeva should receive care by a dentist or an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition. ADVERSE REACTIONS: The following adverse reactions are discussed below and elsewhere in the labeling: s (YPOCALCEMIA (see Warnings and Precautions) s /STEONECROSIS OF THE *AW (see Warnings and Precautions) The most common adverse reactions in patients receiving Xgeva (per-patient incidence greater than or equal to 25%) were fatigue/asthenia, hypophosphatemia, and nausea (see Table 1). The most common serious adverse reaction in patients receiving Xgeva was dyspnea. The most common adverse reactions resulting in discontinuation of Xgeva were osteonecrosis and hypocalcemia. Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in other clinical trials and may not reďŹ‚ect the rates observed in practice. The safety of Xgeva was evaluated in three randomized, double-blind, double-dummy trials (see Clinical Trials  in full Prescribing Information) in which a total of 2841 patients with bone metastasis from prostate cancer, breast cancer, or other solid tumors, or lytic bony lesions from multiple myeloma received at least one dose of Xgeva. In Trials 1, 2, and 3, patients were randomized to receive either 120 mg of Xgeva every 4 weeks as a subcutaneous injection or 4 mg (dose adjusted for reduced renal function) of zoledronic acid every 4 weeks by intravenous (IV) infusion.
prolapse to receive a either a midurethral sling (165 patients) or sham incisions (172 patients) during surgery. The women did not have symptoms stress urinary incontinence preoperatively. At 12 months, 27.3% of the sling recipients had urinary incontinence compared with 43% of patients in the Entry criteria included serum calcium (corrected) from 8 to 11.5 mg/dL (2 to 2.9 mmol/L) and creatinine clearance 30 mL/min or greater. Patients who had received IV bisphosphonates were excluded, as were patients with prior history of ONJ or osteomyelitis of the jaw, an active dental or jaw condition requiring oral surgery, non-healed dental/oral surgery, or any planned invasive dental procedure. During the study, serum chemistries including calcium and phosphorus were monitored every 4 weeks. Calcium and vitamin D supplementation was recommended but not required. The median duration of exposure to Xgeva was 12 months (range: 0.1 â€“ 41) and median duration onstudy was 13 months (range: 0.1 â€“ 41). Of patients who received Xgeva, 46% WERE FEMALE %IGHTY lVE PERCENT WERE 7HITE (ISPANIC,ATINO !SIAN and 3% Black. The median age was 63 years (range: 18 â€“ 93). Seventy-ďŹ ve percent of patients who received Xgeva received concomitant chemotherapy.
sham group, a difference that translated into a significant 52% decreased risk of urinary incontinence after adjusting for potential confounders, in the New England Journal of Medicine (2012; 366:2358-2367). During follow-up, 12 women in the sling group (7.3%) underwent treatment for anticancer treatments affected denosumab systemic exposure and pharmacodynamic effect. Serum denosumab concentrations at 1 and 3 months were not altered by concomitant chemotherapy and/or hormone therapy. The median reduction in uNTx/Cr from baseline to month 3 was similar between patients receiving concomitant chemotherapy and/or hormone therapy (see Clinical Pharmacology [12.2] in full Prescribing Information).
USE IN SPECIFIC POPULATIONS: Pregnancy: Category C. There are no adequate and well-controlled trials of Xgeva in pregnant women. Use Xgeva during pregnancy only if the potential beneďŹ t justiďŹ es the potential risk to the fetus. Encourage women who become pregnant during Xgeva treatment to enroll in Amgenâ€™s Pregnancy Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800772-6436) to enroll. In an embryofetal developmental study, cynomolgus a Table 1. Per-patient Incidence of Selected Adverse Reactions of Any monkeys received subcutaneous denosumab weekly during organogenesis at Severity (Trials 1, 2, and 3) doses up to 6.5-fold higher than the recommended human dose of 120 mg every 4 weeks, based on body weight (mg/kg). No evidence of maternal toxicity Xgeva Zoledronic Acid OR FETAL HARM WAS OBSERVED (OWEVER THIS STUDY ONLY ASSESSED FETAL TOXICITY Body System n = 2841 n = 2836 during the ďŹ rst trimester, and fetal lymph nodes were not examined. Potential % % adverse developmental effects resulting from exposures during the second and third trimesters have not been assessed in animals (see Nonclinical Toxicology GASTROINTESTINAL [13.2] in full Prescribing Information). In genetically engineered mice in which Nausea 31 32 the gene for RANK ligand (RANKL) has been deleted (a â€œknockout mouseâ€?), the Diarrhea 20 19 absence of RANKL caused fetal lymph node agenesis and led to postnatal impairment of dentition and bone growth. Pregnant RANKL knockout mice also showed altered maturation of the maternal mammary gland, leading to GENERAL impaired lactation postpartum (see Use in Nursing Mothers). 45 46 Fatigue/ Asthenia Nursing Mothers. It is not known whether Xgeva is excreted into human milk. INVESTIGATIONS Because many drugs are excreted in human milk and because of the potential 18 9 (YPOCALCEMIAb for serious adverse reactions in nursing infants from Xgeva, a decision should 32 20 (YPOPHOSPHATEMIAb be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Maternal exposure to Xgeva NEUROLOGICAL during pregnancy may impair mammary gland development and lactation based on animal studies in pregnant mice lacking the RANK/RANKL signaling 13 14 (EADACHE pathway that have shown altered maturation of the maternal mammary gland, leading to impaired lactation postpartum (see Nonclinical Toxicology [13.2] in RESPIRATORY full Prescribing Information). 21 18 Dyspnea 15 15 Cough Pediatric Use. The safety and effectiveness of Xgeva in pediatric patients have not been established. Treatment with Xgeva may impair bone growth in a Adverse reactions reported in at least 10% of patients receiving Xgeva in children with open growth plates and may inhibit eruption of dentition. In neonatal rats, inhibition of RANKL with a construct of osteoprotegerin bound to Trials 1, 2, and 3, and meeting one of the following criteria: Fc (OPG-Fc) at doses less than or equal to 10 mg/kg was associated with s !T LEAST GREATER INCIDENCE IN 8GEVA TREATED PATIENTS OR inhibition of bone growth and tooth eruption. Adolescent monkeys dosed with s "ETWEEN GROUP DIFFERENCE EITHER DIRECTION OF LESS THAN AND MORE THAN denosumab at 5 and 25 times (10 and 50 mg/kg dose) higher than the 5% greater incidence in patients treated with zoledronic acid compared to recommended human dose of 120 mg subcutaneously every 4 weeks (based on placebo (US Prescribing Information for zoledronic acid) body weight mg/kg) had abnormal growth plates (see Nonclinical Toxicology b Laboratory-derived and below the central laboratory lower limit of normal [8.3 â€“ [13.2] in full Prescribing Information). 8.5 mg/dL (2.075 â€“ 2.125 mmol/L) for calcium and 2.2 â€“ 2.8 mg/dL (0.71 â€“ Geriatric Use. Of patients who received Xgeva in Trials 1, 2, and 3, 1260 0.9 mmol/L) for phosphorus] (44%) were 65 years of age or older. No overall differences in safety or efďŹ cacy were observed between these patients and younger patients. Severe Mineral/Electrolyte Abnormalities s 3EVERE HYPOCALCEMIA CORRECTED SERUM CALCIUM LESS THAN MGD, OR LESS THAN Renal Impairment. In a trial of 55 patients without cancer and with varying degrees 1.75 mmol/L) occurred in 3.1% of patients treated with Xgeva and 1.3% of of renal function who received a single dose of 60 mg denosumab, patients with a patients treated with zoledronic acid. Of patients who experienced severe creatinine clearance of less than 30 mL/min or receiving dialysis were at greater risk hypocalcemia, 33% experienced 2 or more episodes of severe hypocalcemia of severe hypocalcemia with denosumab compared to patients with normal renal and 16% experienced 3 or more episodes (see Warnings and Precautions and function. The risk of hypocalcemia at the recommended dosing schedule of 120 mg Use in SpeciďŹ c Populations). every 4 weeks has not been evaluated in patients with a creatinine clearance of less s 3EVERE HYPOPHOSPHATEMIA SERUM PHOSPHORUS LESS THAN MGD, OR LESS than 30 mL/min or receiving dialysis (see Warnings and Precautions, Adverse than 0.6 mmol/L) occurred in 15.4% of patients treated with Xgeva and Reactions, and Clinical Pharmacology [12.3] in full Prescribing Information). 7.4% of patients treated with zoledronic acid. OVERDOSAGE: There is no experience with overdosage of Xgeva. Osteonecrosis of the Jaw PATIENT COUNSELING INFORMATION: In the primary treatment phases of Trials 1, 2, and 3, ONJ was conďŹ rmed in Advise patients to contact a healthcare professional for any of the following: 1.8% of patients in the Xgeva group and 1.3% of patients in the zoledronic acid group (see Warnings and Precautions). When events occurring during an s 3YMPTOMS OF HYPOCALCEMIA INCLUDING PARESTHESIAS OR MUSCLE STIFFNESS extended treatment phase of approximately 4 months in each trial are included, twitching, spasms, or cramps (see Warnings and Precautions and Adverse the incidence of conďŹ rmed ONJ was 2.2% in patients who received Xgeva. The Reactions) median time to ONJ was 14 months (range: 4 â€“ 25). s 3YMPTOMS OF /.* INCLUDING PAIN NUMBNESS SWELLING OF OR DRAINAGE FROM the jaw, mouth, or teeth (see Warnings and Precautions and Adverse Immunogenicity. As with all therapeutic proteins, there is potential for Reactions) immunogenicity. Using an electrochemiluminescent bridging immunoassay, s 0 ERSISTENT PAIN OR SLOW HEALING OF THE MOUTH OR JAW AFTER DENTAL SURGERY (see less than 1% (7/2758) of patients with osseous metastases treated with denosumab doses ranging from 30 â€“ 180 mg every 4 weeks or every 12 Warnings and Precautions) weeks for up to 3 years tested positive for binding antibodies. No patient with s 0REGNANCY OR NURSING (see Use in SpeciďŹ c Populations) positive binding antibodies tested positive for neutralizing antibodies as Advise patients of the need for: assessed using a chemiluminescent cell-based in vitro biological assay. There was no evidence of altered pharmacokinetic proďŹ le, toxicity proďŹ le, or clinical s 0ROPER ORAL HYGIENE AND ROUTINE DENTAL CARE response associated with binding antibody development. The incidence of s )NFORMING THEIR DENTIST THAT THEY ARE RECEIVING 8GEVA antibody formation is highly dependent on the sensitivity and speciďŹ city of the s !VOIDING INVASIVE DENTAL PROCEDURES DURING TREATMENT WITH 8GEVA assay. Additionally, the observed incidence of a positive antibody (including ÂŽ . Patients should neutralizing antibody) test result may be inďŹ‚uenced by several factors, Advise patients that denosumab is also marketed as Prolia ÂŽ including assay methodology, sample handling, timing of sample collection, inform their healthcare provider if they are taking Prolia . concomitant medications, and underlying disease. For these reasons, Amgen Manufacturing Limited, a subsidiary of Amgen Inc. comparison of antibodies to denosumab with the incidence of antibodies to other products may be misleading. One Amgen Center Drive DRUG INTERACTIONS: No formal drug-drug interaction trials have been conducted with Xgeva. In clinical trials in patients with breast cancer metastatic to bone, Xgeva was administered in combination with standard anticancer treatment. Serum denosumab concentrations at 1 and 3 months and reductions in the bone turnover marker uNTx/Cr (urinary N-terminal telopeptide corrected for creatinine) at 3 months were similar in patients with and without prior intravenous bisphosphonate therapy. There was no evidence that various
Thousand Oaks, California 91320-1799 ÂŠ2011 Amgen Inc. All rights reserved. Printed in USA.
urinary incontinence compared with 19 (11%) in the sham group. The researchers, led by John T. Wei, MD, of the University of Michigan in Ann Arbor, calculated that 6.3 patients would need to be treated with a sling to prevent on case of urinary incontinence at 12 months. Sling recipients had significantly higher rate of bladder perforation and urinary tract infection than the sham group (6.7% vs. 0% and 31% vs. 18.3%, respectively). Sling recipients also had significantly higher rates of major bleeding complications (3.7% vs. 0%) and incomplete bladder emptying six weeks postoperatively (3.7% vs. 0%). â€œCounseling those who are planning to undergo vaginal-prolapse surgery should weigh the benefits and the risks of sling placement,â€?Dr. Weiâ€™s group concluded. They noted that the incidence of postoperative incontinence may differ according to the type of anterior repair or apical suspension, â€œbut our study was not powered to assess these subgroups.â€? â–
Renal Graft Loss Down in Children BOSTONâ€”Pediatric renal graft survival has improved over time, researchers reported at the 2012 American Transplant Congress. Dorry L. Segev, MD, and colleagues at Johns Hopkins University School of Medicine in Baltimore analyzed graft survival among 16,266 patients younger than 18 years who received a kidney-only transplant from 1987 to 2010. One-, five-, and 10-year graft survival was 80.9%, 58.3%, and 44.5% for transplants performed in 1987 compared with 93.4%, 73.6%, and 55.5% for transplants performed in 2010. With each year, the risk of graft loss decreased by 4%, after adjusting for possible confounders. Similar trends were observed for both living
ÂŠ2011 Amgen Inc. All rights reserved. 63850-R1-V1 12/11
REFERENCES: 1. Saad F, Gleason DM, Murray R, et al, for the Zoledronic Acid Prostate Cancer Study Group. Long-term efďŹ cacy of zoledronic acid for the prevention of skeletal complications in patients with metastatic hormone-refractory prostate cancer. J Natl Cancer Inst. 2004;96:879-882. 2. Ibrahim A, Scher N, Williams G, et al. Approval summary for zoledronic acid for treatment of multiple myeloma and cancer bone metastases. Clin Cancer Res. 2003;9:2394-2399. 3. Yu EY, Nathan FE, Higano CS. Role of detection of metastatic disease as a leading cause of screening failure in an ongoing phase III trial of zibotentan versus placebo in patients with nonmetastatic castration-resistant prostate cancer (CRPC). J Clin Oncol. 2011;29(suppl 7). Abstract 135. 4. Scher HI, Morris MJ, Kelly WK, Schwartz LH, Heller G. Prostate cancer clinical trial end points: â€œRECISTâ€?ing a step backwards. Clin Cancer Res. 2005;11:5223-5232. 5. Tannock IF, de Wit R, Berry WR, et al, for the TAX 327 Investigators. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004;351:1502-1512. 6. Petrylak DP, Tangen CM, Hussain MHA, et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med. 2004;351:1513-1520. 7. XGEVAÂŽ (denosumab) prescribing information, Amgen. 8. Saad F, Gleason DM, Murray R, et al, for the Zoledronic Acid Prostate Cancer Study Group. A randomized, placebocontrolled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst. 2002;94:1458-1468.
and deceased donors. Graft survival improvements were significantly greater in the first year after transplantation. After twelve months post-transplant, the risk of graft loss decreased by 8% with each successive year, whereas beyond one year, the risk decreased by 2% with each successive year. â–
Renal & Urology News 29
Legal Issues in Medicine After a urologist settles, an anesthesiologist is left as the only defendant in a case involving an amputated gangrenous penis BY ANN W. LATNER, JD
Elective surgery and complications The procedure was scheduled and an anesthesiologist, Dr. A, 46, was retained to provide anesthesia. Dr. A spoke briefly to the patient before putting him under, and then Dr. L performed the implant surgery. The procedure was completed as expected, with no immediate problems. However, a little over a week post-surgery, Mr. E developed a severe infection leading to gangrene of the penis. Despite attempts to salvage the organ, it eventually required amputation. When Mr. E recovered from the amputation, he and his wife sought the counsel of a plaintiff’s attorney to determine whether they could sue. The attorney called in a consulting physician to go
urologist never even noted the patient’s blood glucose levels in the chart, or gave the patient any information regarding the effect of diabetes on wounds and the likelihood of infection.”
Legal advice varies Armed with this information, the plaintiff’s attorney filed a lawsuit on behalf of Mr. and Mrs. E against both Dr. L, and Dr. A, the anesthesiologist. Both physicians consulted with attorneys provided by their malpractice insurance, but each received different advice. Dr. L’s attorney advised him to settle the case out of court. “Unfortunately,” the attorney said, “we would be hard-pressed to prove that Mr. E was an appropriate candidate for surgery with his medical history. The jury would wonder why you didn’t advise him about the diabetes possibly being an issue.” Dr. L hung his head. “I have a lot of cases,” he muttered. Dr. A, however, received different advice from his attorney. “I don’t think you should settle,” his attorney said. “Isn’t it the urologist’s job to clear the patient for surgery?” Dr. A nodded. “Yes, I’m not the one who does it. My interaction with the patient is brief, and ends once the epidural catheter is removed.”
Plaintiff’s attorney argues that given the patient’s comorbid conditions, he never should have been cleared for penile implant surgery. over the medical records. After reviewing the records, the expert physician told the attorney that Mr. E should never have been cleared for surgery. “You have here a patient with both high blood pressure and uncontrolled diabetes,” the doctor said. “Every physician knows that uncontrolled diabetes makes a patient far more prone to infections. Mr. E was not in good enough physical shape for such an operation, and he should not have been cleared for it. It appears that the
“Okay,” the attorney replied. “We’ll just play this out.” Dr. L, the urologist, settled out of court with the plaintiff for an unspecified sum, leaving only Dr. A as a defendant in the case. But the plaintiff pushed on, and the case went to trial. The trial required several days of testimony. The plaintiff argued that the anesthesiologist was the only one who cleared him for surgery, and that the anesthesiologist should be held liable
r. L, 52, was an urologist with a private practice, who specialized in the treatment of erectile dysfunction. One of his patients was Mr. E, 60, who came in complaining that his inability to maintain an erection was interfering with his marriage. Dr. L went over various options with the patient, who eventually decided on elective penile implant surgery to remedy the problem. In his patient intake form, Mr. E noted that he had high blood pressure and diabetes, but Dr. L did not mention that this could be an issue.
After a penile implant, a dangerous infection set in that caused irreparable damage.
for his unfortunate outcome. The defense argued that it wasn’t the anesthesiologist’s job to clear anyone for surgery, and that the plaintiff’s infection was probably caused by his failure to follow post-operative instructions. The case went to the jury, which deliberated for half an hour before finding the anesthesiologist not liable for the plaintiff’s amputation.
Legal background It is quite common for a plaintiff to sue numerous defendants in a medical malpractice case. Often, several parties are sued as part of a case. A jury often looks at the percentage of liability for which each defendant is responsible— assuming the defendants are found liable. In this case, only two physicians were sued. Once the urologist, who should legitimately have been sued, settled out of court, the entire case was resting on the anesthesiologist. There simply was not enough evidence to find the anesthesiologist liable. In fact, even pursuing the case against the anesthesiologist, as only defendant left, was a waste of the court’s time and resources. Protecting yourself Clearly, Dr. L did not properly communicate with his patient. He was seemingly unaware of the patient’s other health
problems, indicating that he did not conduct a proper examination or take a thorough enough medical history. After the surgery, since he had not taken the time to familiarize himself with the patient’s co-existing medical problems, Dr. L did not properly instruct him to be aware of infection or how to avoid it. Dr. L cleared the patient for surgery without without taking into consideration how his diabetes or hypertension might affect surgical outcomes. It is essential to take the time to get a thorough medical history and to communicate properly with your patient. Doing that might have avoided this very unfortunate outcome. Dr. A, the anesthesiologist, had the misfortune of being the only one left “holding the bag” once the urologist settled out of court. While it would have made sense for the plaintiff to drop the case against Dr. A once the urologist was no longer a party, a plaintiff often wants his day in court, whether it is against the right defendant or not. ■ Ms. Latner, a former criminal defense attorney, is a freelance medical writer in Port Washington, N.Y. Cases presented are based on actual occurrences. Names of participants and details have been changed. Cases are informational only; no specific legal advice is intended.
Malpractice News $120 Million Awarded to Patient in NY Malpractice Lawsuit A woman who suffered brain damage and permanent incapacitation after being treated at three New York area hospitals was awarded close to $120 million by a Bronx jury in one of the largest awards ever issued in a New York malpractice case. The patient, a 45-year old mother of two, sought treatment for a seizure disorder in 2004. The lawsuit alleged that in the course of less than a month, three hospitals and their medical staff mismanaged the patient’s care. The patient developed an allergic reaction to the anti-seizure medication prescribed for her, causing swelling in her face, eyes, and throat. She was later diagnosed with erythema multiforme (Stevens-Johnson syndrome), a life-threatening skin condition, which can lead to sepsis and organ failure. In this case, the patient ultimately suffered irreversible brain damage. The ruling attributed primary responsibility to two New York City hospitals according to a report in The New York Times. Jacobi Medical Center in the Bronx was charged with 50% of the responsibility and 40% went to Kings County Hospital Center in Brooklyn. Another 5% of liability was attributed to Brookdale University Hospital and Medical Center
© SCIENCE PHOTO LIBRARY
An adverse reaction to a medication caused irreversible brain damage in a mother of two.
in Brooklyn, and 4% to one Brookdale’s neurologists. In a strange twist, which the plaintiff’s attorney attributed to a “jury misunderstanding,” the jury also attributed 1% of the fault to the patient herself. Although the patient earned less
than $40,000 a year as a claims adjuster, the jury awarded her $10 million in lost earnings. The defense attorney argued that medical personnel had mismanaged the patient’s medications, failed to respond swiftly to a series of medical crises, and had not adequately provided essential treatments. According to counsel for the New York City Health and Hospitals Corporation, the city plans to appeal. The corporation’s deputy counsel, Suzanne Bundi noted that, “the amount of this judgment is not consistent with the facts and the law.”
Physicians Win Most Suits, But Battles are Lengthy Most medical malpractice cases in the United States are dismissed before trial, but even so, cases often linger for months or years before dismissal. A recent study, published in the Archives of Internal Medicine (2012;172:892894), revealed new information on the proportion of medical malpractice claims resulting in litigation, litigated claims and resolution according to specialty, and the timeframe for resolving varying types of claims. Researchers led by Anupam B. Jena, MD, PhD, of Massachusetts General Hospital and Harvard Medical School in Boston, examined over 10,000 malpractice claims against physicians that were resolved between 2002 and 2005. Only 55% of the total claims resulted in actual lawsuits. Of those lawsuits, more than half were dismissed by the court. Most of the remaining lawsuits were resolved prior to trial, and of those that went to court, less than 5% ended with a verdict. Verdicts went in favor of the physician approximately 80% of the time, the study showed. According to Dr. Jena, what was most striking in the findings was the length of time it took for liability cases to be resolved—even cases that were dismissed. On average, malpractice suits took longer than 20 months to be dismissed by the court. Litigated suits that were resolved pre-verdict took more than 28 months to come to a point of decision. And cases that went through a full trial typically took over three
BY ANN W. LATNER, JD
years—39 months on average—when they resolved in favor of the physician, and almost four years—44 months— when the patient was the victor. The study also looked at the degree to which specialization affected liability actions. Internists and medicine-based subspecialists had the highest rate of dismissals (61.5%), whereas pathologists were least likely to have cases dismissed (36.5%). Dr. Jena noted that this finding was not a surprise, as pathology lawsuits generally stem from the failure to diagnose a disease. Furthermore, the study showed that the frequency of claims ending in a trial verdict was low across specialties. Internists were not likely to face a jury, with only 3 % of their malpractice cases ending in a verdict. Falling beneath them were anesthesiologists, with a mere 2% of their cases ending in a jury decision. The study results were consistent with previous studies on medical liability resolution. “Part of what is surprising is how long this whole process takes,” Dr. Jena said. “When court cases last a long time, two groups of people are hurt—both patients and physicians. It’s also very difficult for physicians who have a malpractice case looming over their heads.”
Including Patient Photos in EMRs Reduces Medical Errors One of the most common causes of medical error encountered in current electronic medical record (EMR) use is that a providers are placing incorrect orders in the patient’s EMR, a recent study noted (Pediatrics 2012 [Epub ahead of print]). According to the study, e-records have not entirely eliminated human error. The study examined whether including a patient photograph on a verifi cation screen in the EMR would reduce such errors. A quality improvement program at Children’s Hospital Colorado in 2009 found that misplaced orders were, in fact, the second most common reason that patients received inappropriate care—making up 24% of reported errors. To cut down on such
errors, the hospital changed its computer system so that all orders for tests or treatments triggered an “order verification screen” that included a photograph of the pediatric patient.
© STOCKPHOTO / SEAN LOCKE
30 Renal & Urology News
Using photographs in the electronic records of pediatric patients has been shown to minimize medical mistakes.
The new system proved highly effective. In 2010, the hospital had a dozen incidents where a child received care intended for another patient due to misplaced orders. In 2011, that number had dropped to three, and in all three cases there was no photo in the child’s EMR record. Furthermore the program showed that in EMRs that contained a photo of the patient, there was not a single instance of misplaced or mistaken orders. Daniel Hyman, MD, the chief quality officer at the Colorado, hospital |and lead researcher explained that physicians may have multiple records open onscreen at one time and think they are writing in one patient’s chart when they are really entering an order into another. He said that |his hospital added the photos by using a digital camera, and that other hospitals could easily do the same using inexpensive technology. However, Dr. Hyman noted that one problem that sometimes comes up is that some parents don’t want their child’s picture incorporated for privacy issues. Making parents aware that the use of a photo is to aid their children’s safety might avoid that problem. ■ Ms. Latner, a former criminal defense attorney, is a freelance medical writer in Port Washington, N.Y.
Renal & Urology News 31
An Update: Radiation or Surgery for Prostate Cancer The management of patients with high-risk prostate cancer represents one of the biggest challenges today, with little consensus on optimal treatment
Release Date: August 2012 Expiration Date: August 2013 Estimated time to complete the educational activity: 1 hour
BY STEPHEN A. BOORJIAN, MD
This activity is jointly sponsored by Medical Education Resources and Haymarket Medical Education. STATEMENT OF NEED: Urologists and other healthcare professionals caring for patients with prostate cancer need to assess the relative efficacy and toxicity of surgery versus radiation for the prostate cancer patient. Providers should also be up-to-date on comparative analyses of oncologic outcomes for various prostate cancer treatment modalities and quality of life measures. TARGET AUDIENCE: This activity has been designed to meet the educational needs of urologists and other clinicians involved in the treatment of patients with prostate cancer. EDUCATIONAL OBJECTIVES: After completing the activity, the participant should be better able to: • Compare oncologic outcomes following radical prostatectomy versus radiation therapy for prostate cancer. • Assess quality of life outcomes for prostate cancer patients undergoing either radical prostatectomy or radiation therapy. ACCREDITATION STATEMENT: This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of Medical Education Resources (MER) and Haymarket Medical Education. MER is accredited by the ACCME to provide continuing medical education for physicians. CREDIT DESIGNATION: Medical Education Resources designates this enduring material for a maximum of 1.0 AMA PRA Category 1 CreditTM. Physicians should claim only the credit commensurate with the extent of their participation in the activity. DISCLOSURE OF CONFLICTS OF INTEREST: Medical Education Resources ensures balance, independence, objectivity, and scientific rigor in all its educational programs. In accordance with this policy, MER identifies conflicts of interest with its instructors, content managers, and other individuals who are in a position to control the content of an activity. Conflicts are resolved by MER to ensure all scientific research referred to, reported, or used in a CME activity conforms to the generally accepted standards of experimental design, data collection, and analysis. MER is committed to providing its learners with high-quality CME activities that promote improvements or quality in health care and not a commercial interest. The faculty reported the following financial relationships with commercial interests whose products or services may be mentioned in this CME activity: Name of Faculty • Stephen A. Boorjian, MD
Reported Financial Relationship No financial relationships to disclose
The content managers, Jody A. Charnow and Marina Galanakis, of Haymarket Medical Education, and Victoria C. Smith, MD, of Medical Education Resources, have disclosed that they have no relevant financial relationships or conflicts of interest. METHOD OF PARTICIPATION: There are no fees for participating in and receiving CME credit for this activity. During the period August 2012 through August 2013, participants must: 1) read the learning objectives and faculty disclosures, 2) study the educational activity, 3) complete the posttest and submit it online. Physicians may register at www.myCME.com/renalanurologynews, and 4) complete the evaluation form online. A statement of credit will be issued only upon receipt of a completed activity evaluation form and a completed post-test with a score of 70% or better.
he optimal management strategy for men with newly diagnosed, clinicallylocalized prostate cancer (PCa) remains in debate. PCa is second only to lung cancer in mortality burden among men in the United States.1 However, the heterogeneous natural history of the disease, which may be indolent even without treatment,2 together with the notinsignificant risk of treatment-related side effects,3 complicates decision-making. A benefit to treatment (with surgery) has been demonstrated compared to patients managed with watchful waiting in a recent randomized trial.4 In this study, the relative risk of death from PCa among men assigned to radical prostatectomy (RRP) was 0.56.4
Assessing treatment options The majority of U.S. men today do receive active treatment for PCa,5 in the form of either RRP, which may be performed via open, laparoscopic, and robotic-assisted approaches, or radiation therapy (RT),
Stephen A. Boorjian, MD, is Associate Professor in the Department of Urology at the Mayo Clinic in Rochester, Minn. His research interests include high-risk prostate cancer, and he is active in both basic science and clinical investigation designed to optimize outcomes.
which includes both external beam radiation therapy (EBRT) and brachytherapy (BT). Unfortunately, contemporary prospective randomized studies comparing the efficacy and side effects following these treatments are lacking. Two early trials compared these modalities and found a significant reduction in disease progression after RRP.6,7 Nevertheless, the studies have been criticized for relatively small patient numbers (n=97 and 95, respectively) as well as details regarding methodology and reporting.8 A more recent effort to evaluate treatment outcomes in the clinical trial setting was the Surgical Prostatectomy Versus Interstitial Radiation Intervention Trial (SPIRIT), which randomized men to RRP or BT. However, the trial accrued only 56 patients at 31 centers over two years, and was closed early.9 Meanwhile, the Prostate Testing for Cancer and Treatment (ProtecT) study, which includes arms for RRP, EBRT, and watchful waiting, is ongoing and so it will be years before mature data are available for reporting.10 Given the lack of contemporary, largescale randomized trial data comparing the efficacy of different active therapeutic options for PCa, treatment of these patients continues to be largely based upon individual physician experience
32 Renal & Urology News
CME FEATURE and biases. Indeed, an analysis of the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) dataset, a primarily community-based cohort, found that treatment for localized PCa varied considerably with patient age, comorbidity, and socioeconomic status.5 Moreover, substantial variation in management practices existed across clinical sites that was not explained by case-mix or patient factors.5 Thus, it is not surprising that guidelines from both the American Urological Association11 and the National Comprehensive Cancer Network (NCCN)12 for the management of clinically-localized PCa include both surgery and radiation therapy as alternatives, without providing conclusions regarding relative efficacy. Here, then, the purpose is to present for review data from several of the most recent retrospective comparative series that have evaluated outcomes following surgery and radiation, at tertiary referral centers and in larger, population-based datasets, in order to provide an updated assessment of the relative oncologic efficacy and toxicity profiles associated with RRP and RT.
RRP vs. RT:comparative analyses Institutional series Zelefsky and colleagues from Memorial Sloan-Kettering Cancer Center recently performed a retrospective comparison of patients with cT1-T3b PCa treated at their center by highly-experienced clinicians with intensity-modulated external beam RT (n=1,062) or RRP (n=1,318).13 All RT patients received a dose level of â‰Ľ81Gy, and only a minority of RRP patients received postoperative RT (6%) or adjuvant ADT (1%).13 These investigators found that the eight-year probability of freedom from metastatic progression was 97% for RRP patients and 93% for RT patients.13 Moreover, after controlling for clinicopathologic variables, treatment with RRP was associated with a reduced risk of metastases (HR 0.35; p<0.001) and cancer-specific mortality (HR 0.32; p=0.015).13 The improvement in metastatic progression was more substantial for patients with unfavorable-risk disease (7.8% difference at eight years) than for patients with favorable-risk disease (1.9% difference at eight years).13 Importantly, however, high-risk tumors accounted for only 17% of the overall cohort.13 Furthermore, adjuvant androgen deprivation therapy (ADT) was not routinely
used in the high-risk patients treated with RT, despite randomized clinical trial data which has demonstrated a benefit to longterm (i.e., 24-36 months) adjuvant ADT + RT for patients with high-risk PCa.14-19 To assess the comparative outcomes of surgery and radiation specifically for men with high-risk PCa, the Mayo Clinic Prostatectomy Registry and the Fox Chase Cancer Center (FCCC) Radiation Oncology Database were reviewed to identify 1,847 patients with high-risk PCa treated with definitive local therapy in the form of RRP (n=1,238), EBRT alone (n=265), or external-beam RT with long-term (median 22.8 months) adjuvant ADT (n=344) between 19882004.20 For this analysis, high-risk disease was defined according to NCCN guidelines21 as: PSA â‰Ľ20 ng/mL or clinical stage â‰Ľ T3N0M0 or biopsy Gleason score 8-10. Median follow-up was 10.2 years after RRP, 6.0 years after RT + ADT, and 7.2 years after RT alone. These investigators found that, when controlling for case mix and patient variables, patients treated with RT + ADT had a significantly increased risk of all-cause mortality compared to patients who underwent RRP (HR 1.60, p=0.0002).20 Indeed, the 10-year overall survival after RRP was 77%, versus 67% following RT + ADT and 52% after RT alone.20 One potential explanation for this finding is that ADT, which was given more frequently to patients receiving RT than patients treated with RRP, adversely impacted men treated with RT. ADT has been associated with an increased risk of cardiac death, particularly in men with coronary artery disease.22 While the exact mechanism of this interaction is
Indeed, Meng et al found that patients with high-risk PCa treated with radiation therapy were 3.5 times more likely to receive ADT than patients treated with RRP.25 As increasing data have emerged on the adverse consequences of ADT on the quality of life3 and non-cancer morbidity26 of men with PCa, the ability to delay if not avoid ADT may represent a potential advantage to surgery for these patients. RRP affords the ability to facilitate the selective application of secondary therapies in patients confirmed to have pathologically aggressive disease features.27-29 As several independent series24,30 have demonstrated, up to 55% of patients classified as having high-risk disease are in fact found to have organ-confined tumors at surgery. These men may not therefore require additional therapy and may be spared the cost and potential side effects of secondary treatment. The median time from RRP to salvage ADT in the comparative Mayo Clinic/FCCC series was 10.3 years.20 Although the timing of salvage ADT was at the discretion of the surgeon and is not an indicator of treatment success, this suggests that high-risk patients treated with surgery may have long intervals of ADT-free survival. Assessing the comparative outcomes after surgery and RT for patients with high-risk disease remains particularly clinically relevant, for although over the course of the PSA era the proportion of newly-diagnosed PCa patients who would be characterized as having high-risk disease has declined, nevertheless up to 15% of patients continue to present with high-risk tumor features.30,31 In fact, the management of patients with high-risk
One potential benefit of surgery versus RT for patients with high-risk PCa is the ability to obtain pathological staging. unknown, the metabolic effects of ADT may contribute to the comorbidities and risk factors for cardiac death such as diabetes, hypercholesterolemia, and hypertension.23 One potential benefit of surgery versus RT for patients with high-risk PCa is therefore the ability to obtain pathological staging, which, as has been suggested previously,24 may guide the selective application of secondary therapies, and may, for example, delay or avoid the need for ADT.
cancers represents one of the biggest challenges in PCa today, with little consensus on the optimal treatment. A trend toward increasing use of RT and ADT, with a corresponding lower application of RRP, has been noted with increasing PCa disease risk.31 Interestingly, however, the previous retrospective series comparing the outcomes after surgery and radiation for high-risk tumors demonstrated widely disparate results, with several reporting improved outcomes following RRP,32-36
others finding better results following radiation,37,38 and a few,39-41 including a small prospective trial,42 noting equivalent efficacy. However, these studies involved different definitions of high-risk cancer, evaluated disparate outcome measures, and included a relatively limited number of patients, often with short-term followup. Therefore, it remains important, as in the recent studies reviewed here,13,20 to evaluate robust datasets with long-term follow-up to assess the impact of treatment on the endpoint of mortality.
Population-based series Concerns exist regarding the ability to extrapolate results from tertiary referral centers and other treatment settings. Thus, it is important to review outcomes from population-based datasets, which have evaluated comparative survival following surgery and radiation. For example, Cooperberg et al recently analyzed treatment outcomes from the CaPSURE dataset, a national disease registry that is primarily community-based.35 After adjusting for patient age and disease risk, these investigators noted an increased cancer-specific mortality after radiation versus surgery, such that the hazard ratio for death from PCa after RT relative to RRP was 2.21.35 Again, the magnitude of improvement in survival for surgery versus RT increased with increasing disease risk.35 Two other recent series8,43 evaluated comparative outcomes following RRP and RT using the population-based Surveillance, Epidemiology, and End Results (SEER) database, which covers approximately 26% of the U.S. population. Specifically, Liu and colleagues, using SEER-Medicare linked data, identified 5,845 men diagnosed with local/regional PCa at age 65-74 in 1992, with a comorbidity score < 2, who they defined as potential candidates for RRP.8 Of these patients, 2,567 underwent RRP, 2,006 received RT, 302 underwent RRP plus RT, and 970 were managed with watchful waiting.8 The authors found that the 10-year cancer-specific survival was significantly better following RRP (98.1%) than RT (93.8%, p<0.0001).8 Likewise, the 10-year all-cause survival was also higher after RRP (81%) than RT (60.5%, p<0.0001).8 Not surprisingly, men who underwent RRP had significant differences with regard to tumor stage, Gleason score, and comorbidity status compared with men treated with RT.8 Nevertheless, on multivariate analyses controlling for
Renal & Urology News 33
these factors, the hazard ratio for the risk of death from PCa among patients who underwent surgery compared with watchful waiting was 0.17 (95% CI 0.10, 0.28), versus 0.56 (95% CI 0.37, 0.85) for patients who received RT.8 A separate study by Abdollah et al likewise evaluated PCa mortality and other-cause mortality following RRP, RT, and observation using the SEER dataset, from 1988-2006.43 Using a competingrisks survival analysis in 404,604 patients with clinically-localized disease, these investigators found that, for men with low- to intermediate-risk PCa, the lowest cancer-specific and overall mortality rates for men < 80 years old were recorded in RRP patients.43 Moreover, for men with high-risk disease who were < 70 years old, RRP was again associated with the lowest cancer-specific and overall mortality rates.43 For example, the 10-year rate of death from prostate cancer for a man 60-69 years old with a high risk tumor was 7.2% following surgery, compared to 11.3% after RT (p<0.001).43 Interestingly, however, the authors also noted that, between 1988 and 2006, the number of patients treated with RRP decreased from 57.4% to 38.3%, while more patients were treated with RT (28.8-38.1%).43 No meaningful differences were identified for treatment choice according to PCa risk category, suggesting that tumor variables were not the main determinant of treatment modality in this dataset.43 Further investigation into the factors which are responsible for patients’ decision-making with regard to prostate cancer treatment is therefore needed.
Quality of life outcomes In addition to analyses of the comparative oncologic efficacy of surgery and radiation therapy for PCa increasing attention has focused on the relative toxicities of treatments as well. Since the advent of PSA screening, treatment-related impact on quality of life (QoL) is particularly amplified by the younger age at diagnosis for patients with PCa. Unfortunately, little exists in terms of randomized trial data to evaluate QoL measures following RRP and RT. Studies have moreover historically also been limited by a lack of baseline functional assessment of patients. Nevertheless, several recent prospective series have been reported, using validated QoL instruments and incorporating pretreatment functional data, which merit mention here.
© COURTESY OF MAYO CLINIC, ROCHESTER, MINN.
Endorectal MRI of patients with locally-advanced prostate cancer shows: a) suspected extracapsular extension into the neurovascular bundle and b) suspected invasion of the seminal vesicle.
QoL. Treatments have been shown to uniquely affect various outcome measures, with RRP demonstrating a greater impact on urinary continence and erectile function, while radiation, particularly EBRT, resulting in a greater degree of bowel dysfunction. The relative benefit of RRP for irritative-obstructive symptoms, particularly on longer-term follow-up versus EBRT, requires further study. Additional large-scale prospective evaluations, ideally in a randomized clinical trial setting, are needed to provide better evidence for counseling patients regarding the comparative toxicities of the various treatment options for newly-diagnosed PCa.
Conclusions Litwin et al evaluated 580 men with clinically-localized PCa who were undergoing RRP (307), external beam RT (n=78), or BT (n=90).44 Assessments were conducted before and through 24 months after treatment using the Short Form-36 Health Survey (SF-36), which reports scores for physical and mental components, as well as the University of California-Los Angeles Prostate Cancer Index (PCI), which measures urinary, sexual, and bowel habits with function and bother scores. These investigators found that obstructive and irritative urinary symptoms were more common after BT, while men who underwent RRP had worse urinary control and sexual function than either radiation cohort (p<0.001).44 Interestingly, however, beyond four months post-treatment, the proportion of men reporting severe urinary bother did not differ significantly among treatment groups, while beyond eight months post-treatment, the proportion of men reporting severe sexual bother did not differ significantly among treatment groups.44 Bowel dysfunction, meanwhile, was more common among patients who underwent either form of radiation versus RRP (p<0.001).44 A separate study, which has attracted considerable attention, was a multicenter prospective evaluation by Sanda and colleagues.3 These study prospectively measured outcomes reported by 1,201 patients and 625 spouses or partners before and after RRP, BT, or EBRT. Outcome measures included the Service Satisfaction Scale for Cancer Care, as well as the Expanded Prostate Cancer Index Composite (EPIC),45 an QoL instrument that involves 50 items grouped into two urinary subscales (incontinence and irritative-obstructive) and three summary scores (bowel, sexual, and hormonal).
Sexual QoL was adversely affected after each treatment compared to baseline (p<.0.001), with nerve-sparing mitigating some of the adverse effects of RRP.3 While urinary incontinence was noted after surgery, mean scores on urinary irritation or obstruction improved after RRP.3 In fact, at one year after treatment, moderate or worse distress from overall urinary symptoms was reported by 18% of BT patients, 11% in the radiotherapy group, and 7% of RRP patients.3 Both forms of RT were associated with a reduced QoL related to bowel function after treatment, while no change in bowel symptoms was noted after RRP.3 Importantly, the study also found that changes in QoL were significantly associated with the degree of outcome satisfaction among patients and their spouses or partners.3 The Spanish Multicentric Study of Clinically Localized Prostate Cancer prospectively enrolled 435 patients treated with RRP, EBRT, and BT without neoadjuvant or adjuvant hormonal therapy for evaluation.46 QoL was assessed before and at 1, 3, 6, 12, 24, and 36 months after treatment using the SF-36 version 2 and EPIC. Investigators found that, compared with patients undergoing RRP, patients treated with BT or EBRT demonstrated significantly worse urinary irritative-obstructive and bowel scores, respectively, during the last two years of follow-up.46 In fact, among patients with urinary irritative-obstructive symptoms at baseline, improvement was noted in 64% who underwent nerve-sparing RRP.46 Sexual and urinary incontinence deterioration, however, were greater among surgical patients.46 These data suggest that each of the most common PCa treatment modalities has the potential to adversely impact patients’
The ideal assessment of the relative efficacy and toxicity of surgery versus radiation for PCa would be in a prospective clinical trial. However, given the existing lack of relevant outcome data from randomized trials comparing RRP and RT, and the noted difficulties with organizing such studies, observational series remain the primary current means of comparative evaluation. Increasing data from such studies suggest improved survival following surgery, albeit with considerable bias in patient mix and disease characteristics between cohorts inherent to retrospective cohorts. As such, it is important to note that differences in age, comorbidity status, and tumor variables may be responsible for the worse survival noted among patients treated with RT in the series reviewed here. Additionally, the overall risk of cancerspecific mortality 10 years after primary treatment in most patients is relatively low regardless of the primary treatment modality, suggesting the importance of considering competing causes of mortality, as well as the treatment-related toxicities, into discussions regarding PCa management. Continued investigation into the differing impact of treatments on QoL measures3 and non-cancer morbidities26 will be necessary going forward to help determine the optimal approach to PCa treatment for an individual patient. ■ REFERENCES 1. Jemal A, Siegel R, Xu J, et al. Cancer statistics, 2010. CA Cancer J Clin 2010;60:277-300. 2. Lu-Yao GL, Albertsen PC, Moore DF, et al. Outcomes of localized prostate cancer following conservative management. JAMA 2009;302:1202-1209. 3. Sanda MG, Dunn RL, Michalski J, et al. Quality of life and satisfaction with outcome among postate-cancer survivors. N Engl J Med 2008;358:1250-1261. 4. Bill-Axelson A, Holmberg L, Ruutu M, et al. Scandinavian Prostate Cancer Group Study No. 4. Radical prostatec-
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CME FEATURE tomy versus watchful-waiting in early prostate cancer. N Engl J Med 2005;352:1977-1984. 5. Cooperberg MR, Broering JM, Carroll PR. Time trends and local variation in primary treatment of localized prostate cancer. J Clin Oncol 2010;28:1117-1123. 6. Paulson DF. Randomized series of treatment with surgery versus radiation for prostate adenocarcinoma. NCI Monographs 1988;7:127-131. 7. Akakura K, Isaka S, Akimoto S, et al. Long-term results of a randomized trial for the treatment of Stages B2 and C prostate cancer: Radical prostatectomy versus external beam radiation therapy with a common endocrine therapy in both modalities. Urology 1999;54:313-318. 8. Liu L, Coker AL, Du XL, et al. Long-term survival after radical prostatectomy compared to other treatments in older men with local/regional prostate cancer. J Surg Oncol 2008;97:583-591. 9. Wallace K, Fleshner N, Jewett M, et al. Impact of a multi-disciplinary patient education session on accrual to a difficult clinical trial: the Toronto experience with the surgical prostatectomy versus interstitial radiation intervention trial. J Clin Oncol 2006;24:4158-4162. 10. Donovan JL, Lane JA, Peters JA, et al. Development of a complex intervention improved randomization and informed consent in a randomized controlled trial. J Clin Epidemiol 2009;62:29-36. 11. Thompson I, Thrasher JB, Aus G, et al. Guideline for the management of clinically localized prostate cancer: 2007 update. J Urol 2007;177:2106-2131. 12. The National Comprehensive Cancer Center Network. Prostate Cancer V.3.2010. http://www.nccn.org/ professionals/physician_gls/pdf/prostate.pdf. 13. Zelefsky MJ, Eastham JA, Cronin AM, et al. Metastasis after radical prostatectomy or external beam radiotherapy for patients with clinically localized prostate cancer: a comparison of clinical cohorts adjusted for case mix. J Clin Oncol 2010;28:1508-1513. 14. Lawton CA, Winter K, Murray K, et al. Updated results of the phase III radiation therapy oncology group (RTOG) trial 85-31 evaluating the potential benefit of androgen suppression following standard radiation therapy for unfavorable prognosis carcinoma of the prostate. Int J Radiat Oncol Biol Phys 2001;49:937-946. 15. Bolla M, Collette L, Blank L, et al. Long-term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): a phase III randomized trial. Lancet 2002;360:103-108. 16. Hanks GE, Pajak TF, Porter A, et al. Phase III trial of longterm adjuvant androgen deprivation after neoadjuvant hormonal cytoreduction and radiotherapy in locally advanced carcinoma of the prostate: the radiation therapy oncology group protocol 92-02. J Clin Oncol 2003;21:3972-3978. 17. Roach M 3rd, Bae K, Speight J, et al. Short-term neoadjuvant ADT and external-beam radiotherapy for locally advanced prostate cancer: long-term results of RTOG 8610. J Clin Oncol 2008;26:585-591. 18. Bolla M, de Reijke TM, Van Tienhoven G, et al. Duration of androgen suppression in the treatment of prostate cancer. N Engl J Med 2009;360:2516-2527. 19. Horwitz EM, Bae K, Hanks GE, et al. Ten-year follow-up of Radiation Therapy Oncology Group protocol 92-02: A phase III trial of the duration of elective androgen deprivation in locally advanced prostate cancer. J Clin Oncol 2008;26:2497-2504. 20. Boorjian SA, Karnes RJ, Viterbo R, et al. Long-term survival after radical prostatectomy versus external-beam radiotherapy for patients with high-risk prostate cancer. Cancer 2011;Epub ahead of print. 21. Scardino P. Update: NCCN prostate cancer Clinical Practice Guidelines. J Natl Compr Canc Netw 2005;3 (suppl 1):S29-S33. 22. Nanda A, Chen MH, Braccioforte MH, Moran BJ, D’Amico AV. Hormonal therapy use for prostate cancer and mortality in men with coronary artery diseaseinduced congestive heart failure or myocardial infarction. JAMA 2009;302:866-873. 23. Levine GN, D’Amico AV, Berger P, et al. Androgendeprivation therapy in prostate cancer and cardiovascular risk: a science advisory from the American Heart Association, American Cancer Society, and American Urological Association: endorsed by the American Society for Radiation Oncology. CA Cancer J Clin 2010;60:194-201. 24. Kane CJ, Presti JC, Amling CL, et al. Changing nature of high risk patients undergoing radical prostatectomy. J Urol 2007;177:113-117. 25. Meng MV, Elkin EP, Latini DM, et al. Treatment of patients with high risk localized prostate cancer: results form
cancer of the prostate strategic urological research endeavor (CaPSURE). J Urol 2005;173:1557-1561. 26. Smith MR, O’Malley AJ, Keating NL. Diabetes and cardiovascular disease during androgen deprivation therapy for prostate cancer. J Clin Oncol 2006;24:448-4456. 27. Bolla M, van Poppel H, Collette L, et al. Postoperative RT after radical prostatecomy: a randomised controlled trial (EORTC trial 22911). Lancet 2005;366:572-578. 28. Messing EM, Manola J, Yao J, et al. Immediate versus deferred ADT in patients with node-positive prostate cancer after radical prostatectomy and pelvic lymphadenectomy. Lancet Oncol 2006;7:472-479. 29. Thompson IM, Tangen CM, Paradelo J, et al. Adjuvant radiotherapy for pathological T3N0M0 prostate cancer significantly reduces risk of metastases and improves survival : long-term followup of a randomized clinical trial. J Urol 2009;181:956-962. 30. Boorjian SA, Karnes RJ, Rangel LJ, et al. Mayo Clinic validation of the D’Amico risk group classification for predicting survival following radical prostatectomy. J Urol 2008;179:1354-1361. 31. Cooperberg MR, Cowan J, Broering JM, et al. High-risk prostate cancer in the United States, 1990-2007. World J Urol 2008;26:211-218. 32. Tewari A, Divine G, Chang P, et al. Long-term survival in men with high grade prostate cancer: a comparison between conservative treatment, radiation therapy and radical prostatectomy-a propensity scoring approach. J Urol 2007;177:911-915. 33. Nguyen PL, Chen MH, Catalona WJ, Moul JW, Sun L, D’Amico AV. Predicting prostate cancer mortality among men with intermediate to high-risk disease and multiple unfavorable risk factors. Int J Radiat Oncol Biol Phys 2009;73:659-664. 34. Klein EA, Ciezki J, Kupelian PA, Mahadevan A. Outcomes for intermediate risk prostate cancer are there advantages for surgery, external radiation, or brachytherapy? Urol Oncol 2009; 27:67-71. 35. Cooperberg MR, Vickers AJ, Broering JM, Carroll PR. Comparative risk-adjusted mortality outcomes after primary surgery, radiotherapy, or androgen-deprivation therapy for localized prostate cancer. Cancer 2010;116:5226-5234. 36. Jeldres C, Suardi N, Perrotte P, et al. Survival after radical prostatectomy and radiotherapy for prostate cancer: a population-based study. Can Urol Assoc J 2009;3:13-21. 37. Fletcher SG, Mills SE, Smolkin ME, Theodorescu D. Casematched comparison of contemporary radiation therapy to surgery in patients with locally advanced prostate cancer. Int J Radiat Oncol Biol Phys. 2006;66:1092-1099. 38. Arcangeli G, Strigari L, Arcangeli S, et al. Retrospective comparison of external beam radiotherapy and radical prostatectomy in high-risk, clinically localized prostate cancer. Int J Radiat Oncol Biol Phys 2009;75:975-982. 39. D’Amico AV, Whittington R, Kaplan I, et al. Equivalent biochemical failure-free survival after external beam radiation therapy or radical prostatectomy in patients with a pretreatment prostate specific antigen of > 4-20 ng/ml. Int J Radiat Oncol Biol Phys 1997;15:1053-1058. 40. D’Amico AV, Whittington R, Malkowicz SB, et al. Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. JAMA 1998;280:969-974. 41. Kupelian PA, Elshaikh M, Reddy CA, Zippe C, Klein EA. Comparison of the efficacy of local therapies for localized prostate cancer in the prostate-specific antigen era: a large single-institution experience with radical prostatectomy and external-beam radiotherapy. J Clin Oncol 2002;20:3376-3385. 42. Akakura K, Suzuki H, Ichikawa T, et al. A randomized trial comparing radical prostatectomy plus endocrine therapy versus external beam radiotherapy plus endocrine therapy for locally advanced prostate cancer. Jpn J Clin Oncol 2006;36:789-793. 43. Abdollah F, Sun M, Thuret R, et al. A competing-risks analysis of survival after alternative treatment modalities for prostate cancer patients:1988-2006. Eur Urol 2011; 59:88-95. 44. Litwin MS, Gore JL, Kwan L, et al. QoL after surgery, external beam irradiation, or brachytherapy for early-stage prostate cancer. Cancer 2007;109:2239-2247. 45. Wei JT, Dunn RL, Litwin MS, et al. Development and validation of the Expanded Prostate Cancer Index Composite (EPIC) for comprehensive assessment of health-related quality of life in men with prostate cancer. Urology 2000;56:899-905. 46. Pardo Y, Guedea F, Aguiló F, et al. Quality-of-life impact of primary treatments for localized prostate cancer in patients without hormonal treatment. J Clin Oncol 2010;28:4687-4696.
DISCLAIMER: The content and views presented in this educational activity are those of the authors and do not necessarily reflect those of Medical Education Resources or Haymarket Medical Education. The authors have disclosed if there is any discussion of published and/or investigational uses of agents that are not indicated by the FDA in their presentations. The opinions expressed in this educational activity are those of the faculty and do not necessarily represent the views of Medical Education Resources, or Haymarket Medical Education. Before prescribing any medicine, primary references and full prescribing information should be consulted. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patient’s conditions and possible contraindications on dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities. The information presented in this activity is not meant to serve as a guideline for patient management.
CME Post-test Expiration Date: August 2013 Medical Education Resources designates this educational activity for a maximum of 1.0 AMA PRA Category 1 Credit™. Participants should claim only the credit commensurate with the extent of their participation in the activity. Physician post-tests must be completed and submitted online. Physicians may register at no charge at www.myCME.com /renalandurologynews. You must receive a score of 70% or better to receive credit. 1. Prospective, randomized trial data have demonstrated: a. A decreased risk of death due to prostate cancer following RT compared to watchful waiting. b. A decreased risk of death due to prostate cancer following RRP compared to watchful waiting. c. No difference in mortality following RRP compared to watchful waiting. d. A decreased risk of death due to prostate cancer following RT compared to RRP. 2. Recent retrospective institutional and population-based series have demonstrated that, relative to RRP, treatment with RT for prostate cancer is associated with: a. Improved biochemical-recurrence free survival b. Improved metastases-free survival c. Decreased overall survival d. Decreased cancer-specific mortality e. None of the above 3. According to recent comparative studies, the relative cancer-specific survival benefit for surgery compared to radiation when used as primary prostate cancer treatment exists: a. For patients classified as having low-risk disease only b. For patients classified as having high-risk disease only c. For men > 70 years old only d. Across risk group strata for men < 70 years old e. Across risk group strata for men > 70 years old 4. What percentage of newly-diagnosed prostate cancer patients are currently classified according to clinical criteria as having high-risk disease? a. 5% b. 15% c. 30% d. 35% e. 45%
5. High-risk prostate cancer is defined according to the NCCN criteria as: a. Gleason score ≥ 7 b. PSA ≥ 10 c. Clinical stage ≥ T2 d. Gleason score 8-10 or PSA ≥ 20 or clinical stage ≥ T3N0M0 e. Gleason score 8-10 and PSA ≥ 20 and clinical stage ≥ T3N0M0 6. What percentage of contemporary patients classified as having high-risk prostate cancer according to pretreatment criteria are found to have organ-confined disease at the time of radical prostatectomy? a. 10% b. 25% c. 33% d. 55% e. 75% 7. The Expanded Prostate Cancer Index Composite (EPIC) represents an assessment tool for quality-of-life outcomes in prostate cancer patients comprising 50 questions covering: a. Urinary incontinence and urinary irritative-obstructive symptoms b. Bowel symptoms c. Sexual symptoms d. Hormonal symptoms e. All of the above 8. One quality-of-life domain which has consistently been reported to be worse among prostate cancer patients treated with radiation compared to patients treated with surgery is: a. Urinary incontinence b. Bowel function c. Sexual dysfunction d. Hormonal symptoms e. None of the above
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