Renal & Urology News July 2014 Issue

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VOLUME 13, ISSUE NUMBER 7

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PD Offers Early Survival Advantage Patients may benefit from starting on peritoneal dialysis and then switching to hemodialysis DATA SUPPORT PD-TO-HD SWITCH Patients who start renal replacement therapy on peritoneal dialysis have a survival advantage in the first year compared with those who start on hemodialysis, but by the 5th year, HD patients have a better survival rate, according to a new study.

100

80

60

40

20

Peritoneal dialysis Hemodialysis 82.0%

0

76.1%

33.7%

Year 1

54.5%

Year 5

Source: Bikbov B et al. Impact of initial dialysis modality and modality switches on patient survival: A cohort study.

Presented at the ERA-EDTA 51st Congress, Amsterdam. Poster MP564.

Obesity Increases DGF Risk OBESE PATIENTS who undergo kidney transplantation are at higher risk of delayed graft function (DGF) than non-obese patients, but their risk of graft loss and death is the same, according to Brazilian researchers.

Gabriela C. Souza, PhD, of Hospital de Clínicas de Porto Alegre in Porto Alegre, and colleagues conducted a

CME FEATURE

systematic review and meta-analysis of 21 studies that included a total of 9,296 patients who received a kidney transplant. Obese patients had a 41% increased risk of DGF and a twofold increased risk of cardiovascular disease death compared with non-obese patients. Analysis of studies published continued on page 7

Earn 1 CME credit in this issue

Distinguishing primary from secondary FSGS is an important part of patient management.

FSGS: Talking Points for the Practicing Nephrologist PAGE 26

BY JODY A. CHARNOW AMSTERDAM—Peritoneal dialysis (PD) as the initial dialysis modality is associated with a survival advantage over hemodialysis (HD) during the first year, but HD may offer better survival long term, according to data presented at the 51st Congress of the European Renal Association–European Dialysis and Transplant Association.

In a study of 11,021 incident HD and PD patients, Russian researchers examined the impact of initial dialysis modality and modality switches on patient survival rates over 5 years. Boris Bikbov, MD, of A.I. Evdokimov Moscow State University of Medicine and Dentistry in Moscow, and colleagues classified subjects into four groups according to

Parental CVD May Predict Renal Decline

BY JILL STEIN AMSTERDAM—Individuals with a parental history of cardiovascular disease (CVD) are more likely to develop kidney problems than those without such a history, researchers reported at the 51st Congress of the European Renal Association–European Dialysis and Transplant Association.

Juan Jesus Carrero, PhD, of the Karolinska Institutet in Sweden, and colleagues conducted a study of parental CVD history and renal function in a large group of community-based adult men and women enrolled in the Aerobics Center Longitudinal Study (ACLS). The ACLS is a prospective, observational community-based screening program of men and women aged 20 years or older who underwent comprehensive medical examinations, including serum creatinine assessment, at the Cooper Clinic in Dallas, Texas, from April 1994 to February 2004. The analysis included 3,339 individuals

initial modality and long-term (duration more than 30 days) transfer to another modality: HD only, PD only, HD to PD, and PD to HD. Among patients switched from PD to HD, the survival rates at 1, 2, 3, 4, and 5 years were 96%, 89.7%, 82%, 74.6%, and 67.5%, respectively. PD-only patients had a significantly higher survival rate than HD-only patients at 1 year (82% vs. 76.1%), but a significantly lower rate at year 5 (33.7% vs. 54.5%).

Survival rates did not differ significantly between the groups at years 2, 3, and 4.

“Our results suggest that PD was the preferable initial dialysis modality that could be later switched to HD,” the authors concluded. continued on page 7

IN THIS ISSUE 7

Advanced CKD increases the risk of Clostridium difficile infection

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ARDS found to increase the risk of acute kidney injury

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Healthy diets may prevent kidney stones in women

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Uric acid may be a useful outcome predictor in HD patients

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Shock wave lithotripsy has minimal effect on renal function

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Fracture risk is higher in HD patients than PD patients

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Smoking and diabetes raise stroke risk in HD patients

Higher intake of fruits and vegetables cuts kidney stone risk in women.

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VOLUME 13, ISSUE NUMBER 7

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Docetaxel-ADT Combo Ups Survival Major improvement in survival vs. ADT alone seen in patients with newly diagnosed metastatic PCa UPFRONT CHEMOTHERAPY BENEFICIAL A study found that starting patients with newly diagnosed metastatic prostate cancer on both docetaxel and androgen deprivation therapy significantly improves median overall survival.

60

Months

50 40

Entire study population

30

Patients with high-volume disease

20 10

44 0

32.2

ADT alone

57.6

49.2

ADT plus docetaxel

Source: Sweeney CJ, et al. Impact on overall survival (OS) with chemohormonal therapy versus hormonal therapy for hormone-sensitive newly metastatic prostate cancer (mPrCa): An ECOG-led phase III randomized trial. Data presented at the American Society of Clinical Oncology 2014 annual meeting in Chicago.

Obese Pts Live Longer Post-RC ORLANDO, Fla.—Obesity independently predicts improved survival among patients undergoing radical cystectomy (RC) for muscle-invasive bladder cancer, investigators reported at the American Urological Association 2014 annual meeting.

In a retrospective study of 728 patients who underwent RC (median

CME FEATURE

age 70 years), the median overall survival was significantly longer in obese (body mass index [BMI] of 30 kg/m2 or higher) than non-obese patients (4.6 vs. 2.7 years). After adjusting for clinical and pathologic characteristics, obese patients had a 40% decreased risk of death compared with noncontinued on page 7

Earn 1 CME credit in this issue

Distinguishing primary from secondary FSGS is an important part of patient management.

FSGS: Talking Points for the Practicing Nephrologist PAGE 26

BY JODY A. CHARNOW CHICAGO—Starting chemotherapy along with androgen deprivation therapy (ADT) in patients with newly diagnosed metastatic prostate cancer (PCa) improved median overall survival by more than 13 months, according to a study presented at the American Society of Clinical Oncology annual meeting.

In a press conference, lead investigator Christopher J. Sweeney, MBBS, of the Dana-Farber Cancer Institute in Boston, observed, “This is one of the biggest improvements in survival we have seen in a trial involving patients with an adult metastatic solid tumor.”

The study included 790 PCa patients randomized to receive ADT alone (393 patients) or ADT plus docetaxel (397

Circumcision May Decrease Risk of PCa CIRCUMCISION appears to confer a significant protective effect against the development of prostate cancer (PCa) in black men and those circumcised at age 36 years or older, new findings suggest.

Investigators led by Marie-Élise Parent, PhD, Andrea R. Spence, PhD, and Marie-Claude Rousseau, PhD, of INRS-Institut Armand-Frappier (University of Quebec) in Laval, Canada, conducted a case-control study involving 1,590 prostate cancer cases and 1,618 age-matched population controls. In-person interviews were conducted to gather information on sociodemographic, lifestyle, and environmental factors.

Overall, compared with uncircumcised men, circumcised men had a non-significant 11% decreased risk of PCa. Among black men, a group with the highest rate of PCa, circumcision was associated with a significant 60% decreased risk of PCa after adjusting

patients). Subjects had a median age of 63 years. A planned interim analysis showed that the median overall survival (OS) was 44 months in the ADTonly arm compared with 57.6 months in the ADT plus docetaxel arm, a difference that translated into a significant 39% decreased risk of death.

Among men with high-volume disease, the median OS in the ADTonly and combination arms was 32.2 months and 49.2 months, respectively, a 17-month difference that translated into a significant 40% decreased risk of death. In patients with low-volume disease, median OS had not been reached at the time of the analysis, according to investigators. continued on page 7

IN THIS ISSUE 7

Repeat stone treatment is more likely after SWL than ureteroscopy

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Renal cryoablation offers longterm RCC control

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Post-RP statins decrease risk of prostate cancer relapse

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Healthy diets lower the likelihood of kidney stones in women

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Autologous immunotherapy for mRCC shows promise

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Pre-existing hypertension benefits sunitinib recipients

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Prostate tumor size predicts biochemical recurrence risk

Higher intake of fruits and vegetables may prevent kidney stones in women PAGE 14

continued on page 7

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www.renalandurologynews.com JULY 2014

Renal & Urology News 5

FROM THE MEDICAL DIRECTOR EDITORIAL ADVISORY BOARD

Big Data, Transparency, and Accountability

P

hysicians have a love-hate relationship with data. We crave clinical and scientific data, yet we grieve the performance-based data increasingly directed toward us. In her 1969 book On Death and Dying, Elisabeth Kübler-Ross describes the stages of coping with grief. Her model presents an intriguing analogy to physician response to performance data.1 When first faced with publicly reported outcomes, many physicians are unwilling to admit that these results reflect their practice (denial).

Next, a degree of resentment at unsolicited dissemination of information is natural (anger). As medicine is inherently altruistic, many physicians believe such close and public scrutiny is unwarranted, and they argue for further evaluation, improved data collection, and more rigorous severity adjustment prior to public release (bargaining). The consummation of these processes may lead to concerns regarding the negative impact quality reporting may have on autonomy, referral patterns, financial stability, and future litigation risk (depression). In the final stage, Kübler-Ross describes the individual coming to terms with the irrevocability of his/her own mortality/data (acceptance). Whether the majority of physicians will accept that active participation in quality evaluation is necessary to improve health care delivery remains to be seen.

This model may help explain the visceral response most physicians felt to the decision of Centers for Medicare and Medicaid Services to release detailed web-based information on utilization by nearly 900,000 physicians and other providers caring for Medicare beneficiaries (data. cms.gov). In a perspective piece, Brennan et al explain that after an initial request for public comment, which garnered only 130 responses from August 2013 to April 2014, the release was part of a growing commitment toward open data to drive health system improvements.2 So inhale or exhale the data at will, but here is what we physicians should understand. First the data are coming—flaw, limited, and imperfect. We need to engage in the process. Second, guidelines, pathways, and algorithms need not threaten the art of medicine. Variability is best built around standards, which are ours to help define. Third, the bell-shaped curve is a useful measure of performance as it includes two standard deviations from the median. Significant outliers should be analyzed, as they may teach us the good and the bad. Finally, data always represent opportunity, for the system, the doctor, and most importantly, our patients.

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

1 Smaldone MC, Uzzo RG. The Kubler-Ross model, physician distress, and performance reporting. Nat Rev Urol. 2013;10:425-428.

2 Brennan N, Conway PH, Tavenner M. The Medicare Physician Data Release—Context and Rationale. N Engl J Med. 2014 (Epub ahead of print).

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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

Anthony J. Bleyer, MD, MS Professor of Internal Medicine/Nephrology Wake Forest University School of Medicine Winston-Salem, N.C.

Christopher S. Cooper, MD Director, Pediatric Urology Children’s Hospital of Iowa Iowa City

Suphamai Bunnapradist, MD Director of Research Department of Nephrology Kidney Transplant Research Center The David Geffen School of Medicine at UCLA

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 Vice President Regional Medical Operations Professor & Horvitz/Miller Distinguished Chair in Urological Oncology Cleveland Clinic Regional Hospitals Jaime Landman, MD Professor of Urology and Radiology Chairman, Department of Urology University of California Irvine

Csaba P. Kovesdy, MD Chief of Nephrology Memphis VA Medical Center Fred Hatch Professor of Medicine University of Tennessee Health Science Center, Memphis 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.

James M. McKiernan, MD Assistant Professor of Urology Columbia University College of Physicians and Surgeons New York City

Rulan Parekh, MD, MS Associate Professor of Pediatrics and Medicine University of Toronto Robert Provenzano, MD Chief, Section of Nephrology St. John Hospital and Medical Center, Detroit

Kenneth Pace, MD, MSc, FRCSC Assistant Professor Division of Urology St. Michael’s Hospital University of Toronto

Robert S. Rigolosi, MD Director, Regional Hemodialysis Center Holy Name Hospital, Teaneck, N.J.

Ryan F. Paterson, MD, FRCSC Assistant Professor Division of Urologic Sciences University of British Columbia Vancouver, Canada

Lynda Anne Szczech, MD, MSCE Medical Director, Pharmacovigilence and Global Product Development, PPD, Inc. Morrisville, N.C.

Renal & Urology News Staff

Editor Jody A. Charnow Production editor Kim Daigneau Web editor

Stephan Cho

Group art director, Haymarket Medical Jennifer Dvoretz

Production manager Krassi Varbanov

Production director Kathleen Millea Grinder Circulation manager Paul Silver National accounts manager William Canning Publisher Dominic Barone Editorial director

Jeff Forster

Senior VP, medical journals & digital products

Jim Burke, RPh

Senior VP, clinical communications group

John Pal

CEO, Haymarket Media Inc.

Lee Maniscalco

Renal & Urology News (ISSN 1550-9478) Volume 13, Number 7. 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 © 2014.

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Contents

J U L Y

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V O L U M E

Nephrology

ONLINE

this month at renalandurologynews.com Matthew R. Cooperberg, MD, MPH, of the University of California San Francisco, discusses a $9.4 million grant his university received to “transform and revolutionize” prostate cancer treatment.

Healthy Eating May Prevent Stones Increased dietary fiber, fruit, and vegetable intake lowered the risk of kidney stones among women with no history of stones.

15

Uric Acid May Predict Outcomes Serum uric acid levels may be a clinically useful nutritional marker and outcome predictor in patients on maintenance hemodialysis.

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Fracture Risk Varies by Renal Replacement Therapy The risk is 2.6 times and 1.7 times greater in hemodialysis patients than in kidney transplant and peritoneal dialysis patients, respectively.

25

I S S U E

N U M B E R

7

CALENDAR

14

Expert Q&A

1 3 ,

13th Annual Current Concepts in Men’s Health Lake Placid, N.Y. August 15–17 American Society for Radiation Oncology (ASTRO) San Francisco September 14–17 International Continence Society Annual Meeting Rio de Janeiro October 20–24 Kidney Week Philadelphia November 11–16

Smoking Ups Stroke Risk in HD Patients Current smoking is associated with a significant 2.1 times increased risk of ischemic cerebral stroke.

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.

Congratulations to our May winner: Michael Buchanan, MD

Urology

Videos

14

View videos of experts discussing timely topics in nephrology and urology. Our latest include: • Therapeutic advances in mCRPC • Low Estrogen Could Mean Low Testosterone • Dogs Sniff Out Prostate Cancer with 98% Accuracy

News Coverage

Visit our website for timely reports from upcoming meetings.

12

Renal Cryoablation Offers Long-Term RCC Control The procedure is associated with 5-year disease-free, cancer-specific, and overall survival rates of 94.7%, 100%, and 94.5%, respectively.

Post-RP Statins Shown to Reduce PCa Relapse Risk Post-operative statin use is associated with a significantly decreased risk of biochemical recurrence among non-blacks.

20

ADT May Be Safely Deferred After PSA Relapse Immediate ADT offers little or no survival benefit over deferred ADT to prostate cancer patients who experience PSA-only relapse after primary treatment.

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Tumor Size Predicts Biochemical Recurrence Risk Maximal tumor diameter may identify which prostate cancer patients are at very low risk of PSA failure following radical prostatectomy who may not benefit from adjuvant radiation.

26

CME Feature 26

FSGS: Talking Points for the Practicing Nephrologist Fernando C. Fervenza, MD, PhD, Richard J. Glassock, MD, and Sanjeev Sethi, MD, PhD, discuss how to distinguish primary from secondary focal segmental glomerulosclerosis as well as other important clinical challenges.

Departments The finding of an FSGS lesion is the start

of an exploratory process leading to a diagnosis and not an end in itself.

See our CME article on page 26

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5

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From the Medical Director Big data, transparency, and accountability News in Brief Ureteroscopy for stones on the rise

6/20/14 2:59 PM

6 Renal & Urology News

JULY 2014

www.renalandurologynews.com

Contents

J U L Y

2 0 1 4

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V O L U M E

Urology

ONLINE Expert Q&A

Renal Cryoablation Offers Long-Term RCC Control The procedure is associated with 5-year disease-free, cancer-specific, and overall survival rates of 94.7%, 100%, and 94.5%, respectively.

14

Post-RP Statins Shown to Reduce PCa Relapse Risk Post-operative statin use is associated with a significantly decreased risk of biochemical recurrence among non-blacks.

Matthew R. Cooperberg, MD, MPH, of the University of California San Francisco, discusses a $9.4 million grant his university received to “transform and revolutionize” prostate cancer treatment.

20

25

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.

Congratulations to our May winner: Michael Buchanan, MD

Videos

View videos of experts discussing timely topics in nephrology and urology. Our latest include: • Therapeutic advances in mCRPC • Low Estrogen Could Mean Low Testosterone • Dogs Sniff Out Prostate Cancer with 98% Accuracy

News Coverage

Visit our website for timely reports from upcoming meetings.

I S S U E

N U M B E R

7

CALENDAR

12

this month at renalandurologynews.com

1 3 ,

ADT May Be Safely Deferred After PSA Relapse Immediate ADT offers little or no survival benefit over deferred ADT to prostate cancer patients who experience PSA-only relapse after primary treatment.

13th Annual Current Concepts in Men’s Health Lake Placid, N.Y. August 15–17 American Society for Radiation Oncology (ASTRO) San Francisco September 14–17 International Continence Society Annual Meeting Rio de Janeiro October 20–24 Kidney Week Philadelphia November 11–16

Tumor Size Predicts Biochemical Recurrence Risk Maximal tumor diameter may identify which prostate cancer patients are at very low risk of PSA failure following radical prostatectomy who may not benefit from adjuvant radiation.

Nephrology 14

15

Healthy Eating May Prevent Stones Increased dietary fiber, fruit, and vegetable intake lowered the risk of kidney stones among women with no history of stones.

Uric Acid May Predict Outcomes Serum uric acid levels may be a clinically useful nutritional marker and outcome predictor in patients on maintenance hemodialysis.

23

Fracture Risk Varies by Renal Replacement Therapy The risk is 2.6 times and 1.7 times greater in hemodialysis patients than in kidney transplant and peritoneal dialysis patients, respectively.

25

Smoking Ups Stroke Risk in HD Patients Current smoking is associated with a significant 2.1 times increased risk of ischemic cerebral stroke.

26

CME Feature 26

FSGS: Talking Points for the Practicing Nephrologist Fernando C. Fervenza, MD, PhD, Richard J. Glassock, MD, and Sanjeev Sethi, MD, PhD, discuss how to distinguish primary from secondary focal segmental glomerulosclerosis as well as other important clinical challenges.

Departments The finding of an FSGS lesion is the start

of an exploratory process leading to a diagnosis and not an end in itself.

See our CME article on page 26

RUN0714_TOC_URO.indd 6

5

12

From the Medical Director Big data, transparency, and accountability News in Brief Ureteroscopy for stones on the rise

6/20/14 3:00 PM

www.renalandurologynews.com JULY 2014

PD vs. HD

Patients who switched temporarily from hemodialysis to peritoneal dialysis had a 20.4% survival rate at 5 years.

Hemodialysis patients who switched permanently to peritoneal dialysis had a 43.8% survival rate at 5 years.

days), and HD with both a temporary and permanent switch to PD. Patients switched to PD temporarily had the lowest survival rates of the 4 groups (41.7%, 33.1%, 25.5%, 25.5%, and 20.4% at 1, 2, 3, 4, and 5 years, respectively), “probably indicating the failure of both vascular access and peritoneal access,” the

investigators noted. By comparison, HD patients who did not switch had survival rates of 76.3%, 69.6%, 64.4%, 58.9%, and 54.7% at 1, 2, 3, 4, and 5 years respectively. Those who switched permanently to PD had rates of 88.3%, 76.5%, 65%, 51.1%, and 43.8%, and patients who had a temporary and per-

manent switch to PD had rates of 84.6%, 73%, 54.5%, 41.8%, and 34.5%.

In a third study, Greek investigators demonstrated greater survival among HD patients compared with PD patients at 5, 10, and 20 years. Vassilis Filiopoulos, MD, of SismanogleionAmalia Fleming General Hospital in Athens, and colleagues analyzed data from 107 HD patients and 86 PD patients who had at least 3 months of follow-up. The median follow-up duration was 39 months for the HD group and 33 months for the PD group.

The results showed 5-, 10-, and 20-year patient survival rates of 73%, 40%, and 16.5%, respectively, for the HD group versus 45%, 17.5%, and 0%, respectively, for the PD group.

The investigators noted that the survival advantage of HD over PD persisted despite similar co-morbidities between the groups. n

with a proinflammatory environment, with elevated levels of cytokines and chemokines that can mediate the immunologic responses and facilitate DGF.” In addition, technical difficulties encountered while performing a transplant operation in obese patients may lead to a more pronounced ischemiareperfusion injury and thus an elevated risk of DGF. “Obesity should not on its own preclude a patient from being considered for kidney transplantation,” Dr. Souza’s group concluded.

For the study, the investigators defined obesity as a body mass index of 30 kg/m2 or higher.

In a study published in Kidney International (2011;80:218-224), researchers led by Kamyar KalantarZadeh, MD, MPH, PhD, now with the University of California Irvine, reported on a study showing that increasing pretransplant BMI is associated with an increasing risk of DGF. Compared with renal transplant recipients who had a BMI of 22–24.99, those with a BMI of 25–29.99, 30–34.99, and

35 or higher had a 1.30, 1.42, and 2.18 times increased risk of DGF, respectively. The study included 11,836 hemodialysis patients who underwent kidney transplantation from July 2001 to June 2007. A biologically plausible explanation is that obesity is associated with longer operative time and longer warm ischemic time, which are risk factors of DGF, according to the researchers.

Another potential explanation is the link between obesity and increased pro-thrombotic activity and endothelial dysfunction. n

Obesity and DGF Risk continued from page 1

before 2003 showed that obese patients had a 65% increased risk of death at 1 year post-transplant. The researchers found no association between obesity and the risk of death at 1 year post-transplant in studies published after 2003.

“The association of obesity with DGF may be related to immunologic and nonimmunologic factors,” the investigators reported online ahead of print in Transplantation. “Obesity is associated

Parental CVD continued from page 1

with and 9,902 without parental CVD. “Current guidelines recommend that individuals with a positive parental history of CVD or CKD [chronic kidney disease] should be considered at risk of developing CVD or CKD, respectively,” said Dr. Carrero, associate professor of renal medicine. “However, despite similar etiologies, it remains unknown if a broader relationship between these diseases exists across generations.”

Investigators obtained information on premature parental CVD, defined as a parental CVD history before the age of 50 years (either father or mother), determined estimated glomerular filtration rate (eGFR) using the CKD-EPI formula, and defined CKD as an eGFR below 60 mL/ min/1.73 m2.

Results showed that participants with parental CVD had significantly

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© PHOTOS: THINKSTOCK

continued from page 1

Dr. Bikbov told Renal & Urology News that many more PD patients than HD patients in Moscow receive kidney transplants in the first year on dialysis. It is possible that the patients remaining on PD by year 5 are less healthy individuals who could not receive transplants and who have late complications of PD treatment, he said. This potentially could explain the relatively greater survival rate among the HD patients at year 5.

In a separate study of 9,379 incident HD patients, Dr. Bikbov and colleagues looked at the effect of temporarily and permanently switching patients from HD to PD. The researchers classified the patients into 4 groups: HD only, HD with a permanent switch to PD (30 days or more), HD with a temporary switch to PD (less than 30

Renal & Urology News 7

lower eGFR compared with those without parental CVD (69.4 vs. 74.8 mL/min/1.73 m2).

In adjusted analyses, parental CVD was independently associated with a 68% increased odds of having CKD. As many as 3,083 participants in this screening program attended various re-examinations during subsequent years, and investigators assessed the relationship between parental CVD and renal function decline. The eGFR declined by 0.15 mL/min/1.73 m 2 annually among those with parental CVD, which was significantly more rapid that the 0.10 mL/min/1.73 m 2 annual decline among individuals without parental CVD. The findings support “previously unrecognized cross-generational links between both CVD and CKD. This easily retrieved information could be incorporated into community screening programs. Risk-assessment algorithms should establish the vailidity of our findings,” Dr. Carrero said. n

Advanced CKD May Raise Risk of C.Difficile Infection AMSTERDAM—Advanced chronic

filtration rate below 30 mL/min/1.73

kidney disease (CKD) is a risk factor

m2) was associated with higher in-

for Clostridium difficile infection (CDI)

hospital mortality (21.9% vs. 5.0%).

according to study findings presented

Additionally, the use of 2 or more

at the 51st Congress of the European

antibiotics, prior use of vancomycin,

Renal Association-European Dialysis

the presence of pseudomembranous

and Transplant Association.

colitis, elevated white blood cell count,

Kyung Kyu Kim, MD, and collaborators

high C-reactive protein levels, and

at Korea University Anam Hospital in

advanced CKD stages were signifi-

Seoul, Korea, compared 171 patients

cantly associated with poor response

CDI and 342 age- and sex-matched

to initial metronidazole treatment.

control patients without CDI. Stage IV-V

Last year, Surbhi Leekha, MBBS,

CKD not requiring dialysis and end-stage

MPH, and colleagues at Mayo Clinic in

renal disease requiring dialysis were

Rochester, Minn., published a study in

associated with a nearly 2.9 and 4.9

the American Journal of Infection Control

times increased risk of CDI, respectively.

(2013;41:390-393) showing that chronic

Among patients with CDI, more advanced CKD (estimated glomerular

dialysis is among the independent predictors of C. difficile colonization. n

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continued from page 1

obese patients, Gautum Agarwal, MD, and colleagues at the H. Lee Moffitt Cancer Center and Research Institute in Tampa, reported.

The finding of obesity being associated with improved survival has been seen in esophageal and lung cancer as well, Dr. Agarwal told Renal & Urology News.

Obesity was associated with increased operative time (398 vs. 354 minutes for non-obese patients) and increased estimated blood loss (1,045 vs. 926 mL); however, increased BMI did not result in an increased rate of

Circumcision and PCa continued from page 1

for various potential confounders, the researchers reported online ahead of print in BJU International.

Men circumcised at age 36 years or older had a significant 45% decreased risk of PCa compared with uncircumcised men. according to the investigators. Men circumcised within the first year after birth had a 14% decreased risk of PCa. The researchers found no association between circumcision and PCa risk among whites, Asians, and other ancestral groups.

In the black subgroup, 10% of circumcised men had an STI history compared with 28% of uncircumcised

Chemotherapy + ADT continued from page 1

Dr. Sweeney said the data showing a major overall survival benefit are convincing, and this approach should be offered to patients with high-volume metastatic castration-sensitive PCa who are able to tolerate docetaxel. The best candidates include those with liver or lung metastases or more than 4 sites of bone metastases with at least 1 beyond the axial skeleton, he said.

A urologist researcher not involved with the new study, Judd W. Moul, MD, director of the Duke Prostate Center at Duke University Medical Center in Durham, N.C., said he “had heard rumors” that the survival benefit of adding docetaxel to ADT in patients with newly diagnosed metastatic disease was robust, but he was not aware of the actual data until the ASCO annual meeting.

“Now that I see the magnitude of the benefit, I am more excited and,

RUN0714_Cvr.Uro.indd 7

blood transfusions or positive surgical margins (PSM).

Other factors that were independently and significantly associated with increased mortality after RC

Obese patients had increased operative time and estimated blood loss. included PSM, tumor stage, nodal status, increased blood transfusions, stage 4 and 5 chronic kidney disease, and a hospital stay longer than 7 days.

men. White men did not demonstrate such an STI pattern, according to the researchers. Although Dr. Parent and her colleagues adjusted for STI history in their analyses, they noted that residual confounding may potentially explain the protective effect of circumcision among black men.

Previous studies have demonstrated associations between various STIs and an increased PCa risk and that circumcised men have a lower risk of acquiring an STI than uncircumcised men.

The biological mechanism by which circumcision may decrease the acquisition of STIs and thereby potentially decrease PCa risk could be related to penile foreskin anatomy, Dr. Parent’s group explained. The inner surface

frankly, surprised by the results,” Dr. Moul told Renal & Urology News.

“As a urologist, I will now consult my medical oncology partners for all new M1 patients for upfront docetaxel consideration.”

Dr. Moul pointed out that some questions remain unanswered, however. For example, what subgroup of M1 patients, if any, should not receive 6 cycles of docetaxel? Did the degree of testosterone suppression affect results? Would similar or better results be achieved with cabazitaxel? Would more complete ADT along with docetaxel be of added benefit? Does longer-term adjuvant ADT alter the use of docetaxel once a patient progresses to M1 disease?

Nevertheless, Dr. Moul said the new study is a game changer in the management of metastatic PCa, and it adds to all the other good news over the past 5 years related to the introduction of novel agents for treating this stage of disease. n

“Fat can no longer be viewed as having no function,” said Dr. Agarwal, a urologic oncology fellow. “Rather, it acts like an endocrine organ secreting leptin and adiponectin, which are pro- and anti-inflammatory factors. In addition, not all obese patients are the same. There are differences in their metabolic health which may be a cause for the difference in survival.”

The findings of studies looking at the association between BMI and postRC survival have been inconsistent.

For example, in a study that included 847 RC patients, Canadian researchers found that BMI was not prognostic for overall, disease-specific, and recurrence-free survival, according to

© SHUTTERSTOCK

Obesity and RC

Researchers found that circumcision is associated with a significantly lower risk of prostate cancer in black men.

of the foreskin is made of mostly nonkeratinized mucosal epithelium, which is more easily penetrated by microbes than the penile shaft and glans.

Renal & Urology News 7

a recently published report in Urologic Oncology (2014;32:441-448).

A retrospective study of 4,118 patients who underwent RC for urothelial carcinoma of the bladder found that obese patients had a significant 43% and 81% increased risk of cancer-specific and overall mortality, respectively, after adjusting for standard clinicopathologic features, researchers reported in BJU International (2013;111:249-255).

Obese patients also had a significant 67% increased risk of disease recurrence. Patients with a higher BMI were significantly more likely to have a higher tumor grade and positive soft tissue surgical margins compared with patients who had a lower BMI. n

In their discussion of study strengths, the authors noted that their investigation included a large sample size and nearly all participants provided circumcision status. Furthermore, data collection was comprehensive, which allowed for adjustment for many potential confounders.

The study also had limitations. For example, circumcision status was selfreported and largely could not be verified through hospital medical files said.

The investigators also pointed out that they did not know the reasons why adults were circumcised, “limiting our ability to assess whether the protective effect of circumcision was limited to men with medical indications for surgical removal of the foreskin.” n

Repeat Stone Treatment More Likely After SWL ORLANDO, Fla.—Kidney stone patients

created uncertainty regarding the

treated with shock wave lithotripsy (SWL)

comparative effectiveness of these two

are significantly more likely to have

treatment options,” the authors noted

repeat interventions compared with

in their study abstract.

those treated with uretroscopy, research-

In total, 27,031 patients underwent

ers reported at the American Urological

SWL and 31,738 underwent uretros-

Association 2014 annual meeting.

copy. Of these, 6,029 in the ureteros-

In a retrospective cohort, Charles Scales, MD, MSHS, of Duke University School of Medicine in Durham, N.C., and

copy group and 6,464 in the SWL group underwent an additional procedure.

In adjusted analyses, researchers

collaborators studied privately-insured

found that the likelihood of repeat inter-

beneficiaries who went to an emergency

vention was 11% with SWL versus 0.2%

department for kidney stone removal

with ureteroscopy.

from 2002 to 2010. All patients were treated with either SWL or ureteroscopy.

“Advances in ureteroscopy, along

“Among privately-insured beneficiaries requiring procedural intervention to remove a symptomatic stone, repeat

with emerging evidence of reduced

intervention is substantially more likely

efficacy of modern lithotripters, has

following SWL,” they concluded. n

6/20/14 1:14 PM

12 Renal & Urology News

JULY 2014

www.renalandurologynews.com

News in Brief

Please visit us at www.renalandurologynews.com for the latest news updates from the fields of urology and nephrology

Short Takes Ureteroscopy Use for Stones Increasing

thus minimizing the risk of exposing

Researchers who analyzed 194,781

One pump actuation delivers 5.5 mg

kidney stone treatments in Canada

of testosterone. The recommended

over a nearly 20-year period found

dose of Natesto is 11 mg of testos-

increasing use of ureteroscopy (URS)

terone (2 pump actuations, one per

and decreasing use of shock wave

nostril), applied intranasally 3 times

lithotripsy (SWL), according to findings

daily for a total daily dose of 33 mg.

women and children to testosterone.

published online ahead of print in The Journal of Urology.

Michael Ordon, MD, MSc, and col-

Cardiovascular Events Hike CKD Patients’ ESRD Risk

leagues at the University of Toronto

Cardiovascular events increase the

demonstrated that, from July 1, 1991

risk of end-stage renal disease (ESRD)

to December 31, 2010, the use of

and death prior to ESRD among

URS increased from 25% to 59%

patients with stage 3–5 chronic kidney

of procedures and the use of SWL

disease, a study found.

decreased from 69% to 34% of pro-

A team led by David Naimark, MD, of

cedures. In addition, results showed

the University of Toronto, studied 2,964

a significant decrease in the need for

patients referred to a nephrology clinic

ancillary treatment (from 23% to 15%).

at Sunnybrook Health Sciences Centre in Toronto. Cardiovascular events

Nasal Testosterone Therapy Approved

(heart failure, myocardial infarction, or

The FDA has approved the first nasal

and ESRD developed in 318 (11%),

testosterone replacement therapy

according to findings published online

for use in men suffering from condi-

ahead of print in Circulation. In addition,

tions associated with a deficiency or

446 patients (15%) died prior to ESRD.

absence of endogenous testosterone.

A cardiovascular event increased

stroke) occurred in 447 patients (15%)

The product, Natesto (Trimel Phar-

patients’ risk of ESRD and all-cause

maceuticals Corp., Toronto), is self-

mortality prior to ESRD by 5.3 times

administered via a nasal applicator,

and 4.1 times, respectively.

Yes:

Hypochondriacs and the Internet In a recent online poll, Renal & Urology News asked readers the following question: “Do you think the online availability of medical information has increased the number of hypochondriacs?” Here are the poll results based on 107 reponses: 80 70 60 50 40 30 20 10 0

012_RUN0714_NIB.indd 12

71.96%

19.63%

8.41%

Yes

No

Do not know

ARDS Found To Raise Risk of Acute Kidney Injury A

cute respiratory distress syndrome (ARDS) may increase critically ill patients’ risk of acute kidney injury (AKI), a new study suggests.

The study included 8,029 intensive care unit patients, of whom 1,879 had ARDS. AKI developed in 31.3% of patients and occurred significantly more frequently in those with ARDS than in those without it (44.3% vs. 27.4%). After adjusting for confounders, ARDS was independently associated with an 11 times increased risk of AKI compared with patients not on mechanical ventilation (reference group), researchers reported online ahead of print in the Clinical Journal of the American Society of Nephrology. The study, led by Michael Darmon, MD, of Saint Etienne University Hospital in Jarez, France, also identified mechanical ventilation in the absence of ARDS as an independent risk factor for AKI, increasing AKI risk by more than 4-fold. “Our results support the addition of ARDS to the list of risk factors for AKI in critically ill patients,” the authors concluded.

BP Meds Taken At Bedtime Decrease Diabetes Risk H

ypertensive patients without diabetes may be at lower risk of new-onset diabetes if they take at least 1 blood pressure (BP)-lowering medication at bedtime, according to data presented at the American Society of Hypertension annual meeting in New York.

In a prospective, randomized trial of 2,012 hypertensive patients without diabetes mellitus, Ramón C. Hermida, PhD, Campus Universitario, Vigo, Spain, and colleagues found that subjects who took 1 or more BP medications at bedtime had a significant 57% decreased risk of new-onset diabetes than those who took all of their BP medications upon awakening. They also had improved ambulatory BP control.

Diabetes developed in 171 (8.5%) of the 2,012 patients during a median followup of 5.6 years.

The study population had a median age of 52.7 years and consisted of 976 men and 1,036 women.

Renal Cryoablation Offers Long-Term RCC Control L

aparoscopic renal cryoablation of small renal cell carcinoma (RCC) tumors offers optimal and durable cancer control, according to study findings presented at the European Association of Urology 29th annual congress in Stockholm.

In a single-institution study of 189 patients with a median follow-up of 55 months (range 1–156 months), Alessandro Larcher, MD, of Vita-Salute San Raffaele University in Milano, and colleagues found that the procedure is associated with 5-year disease-free, cancer-specific, and overall survival rates of 94.7%, 100%, and 94.5%, respectively, in patients with RCC. The study population had a median tumor size of 21 mm (range 7–40 mm).

Histologic examination revealed 118 RCC tumors, 77 benign lesions, and 20 non-diagnostic specimens.The median time to disease recurrence was 18 months (range 6–48 months).

6/20/14 12:35 PM

14 Renal & Urology News

JULY 2014 www.renalandurologynews.com

Healthy Eating May Prevent Stones

BY JODY A. CHARNOW WOMEN WITH A HIGH consumption of fiber, fruits, and vegetables may lower their risk of kidney stones, according to a new study.

Mathew D. Sorensen, MD, of the University of Washington in Seattle, and colleagues analyzed data from 83,922 postmenopausal women who participated in the prospective Women’s Health Initiative Observational Study. The women had a mean age of 64 years, and 85% of them were Caucasian. Kidney stones developed in 2,937 women (3.5%) during a median follow-up of 8 years.

Among women with no history of kidney stones, multivariate analysis showed that those in the highest quintile of dietary fiber, fruit, and vegetable intake were 22%, 15%, and 22% less likely to report an incident stone event, respectively, compared with women in the lowest quintile, Dr. Sorensen’s group reported online ahead of print in The Journal of Urology. The protective effects were independent of other known risk factors for kidney stones, including body mass index (BMI) and dietary intake of water, sodium, animal protein, and calcium, the investigators reported.

The researchers found no significant protective effect of fiber, fruit, and

vegetable intake among women with a history of kidney stones prior to study participation.

“Our findings suggest that there may be a fundamental difference between women who formed their first stone during this study and those who formed a recurrent stone during this study,” the authors wrote.

Only 3% of women with no history of stones had an occurrence compared with more than 15% of women with a history of stones, the researchers noted.

Thus, women who have their first kidney stone sometime in their 60s might be phenotypically different from women with a history of stones earlier in life.

“Dr. Sorensen and colleagues provide additional evidence suggesting that a diet high in fruits and vegetables may be important in kidney stone prevention,” said Eric N. Taylor, MD, MSc, medical director, Maine Medical Partners Kidney Stone Prevention Program. “In concert with previous data, this study reminds us that a randomized controlled trial is needed to determine the effect on calcium kidney stone recurrence of a diet with higher intake of fruits, vegetables, low-fat dairy products, and whole grains and lower intake of sodium and red and processed meats.”

© THINKSTOCK

Protective effect observed among women with higher intake of dietary fiber, fruits, and vegetables

Diet affects women’s kidney stone risk.

These are the recommendations of the Dietary Approaches to Stop Hypertension (DASH) diet, which is encouraged by the National Heart, Lung, and Blood Institute. In a study published 5 years ago, Dr. Taylor led a team that examined the effect of adhering to a DASH-style diet on kidney stone risk. They analyzed data from 3 large prospective studies: the Health Professionals Follow-up Study (HPFS), which included 45,821 men aged 40 to 75 years and had 18 years of follow-up; the Nurses’ Health Study I (NHS I), which

included 94,108 women aged 30–55 years at enrollment and had 18 years of follow-up; and the Nurses’ Health Study II (NHS II), which included 101,837 women aged 25–42 at enrollment and had 14 years of follow-up.

The investigators constructed a DASH score based on high intake of fruits, vegetables, nuts and legumes, low-fat dairy products, and whole grains, and low intake of sodium, sweetened beverages, and red and processed meats.

A total of 5,645 kidney stones occurred during a combined 50 years of follow-up. Subjects with higher DASH scores had higher intakes of calcium, potassium, magnesium, oxalate, and vitamin C and lower intakes of sodium.

Compared with HPFS subjects in the lowest quintile of DASH score, those in the highest quintile had a 45% reduced risk of kidney stones after adjusting for age, BMI, fluid intake, hypertension, diabetes and other potential confounders, the researchers reported in the Journal of the American Society of Nephrology (2009;20:2253-2259). Among subjects in NHS I (older women) and NHS II (younger women), those in the highest quintile had a 42% and 40% reduced risk of kidney stones compared with those in the lowest quintile. n

Post-RP Statins Shown to Reduce PCa Relapse Risk POST-OPERATIVE use of statins is associated with a decreased risk of biochemical recurrence (BCR) following radical prostatectomy (RP) for prostate cancer, according to a new study.

In a study of 1,146 RP patients— none of whom took statins prior to RP—Emma H. Allott, PhD, of Duke University School of Medicine in Durham, N.C., and colleagues found that post-RP statin use was associated with a significant 36% decreased risk of BCR, after adjusting for clinical and pathological characteristics. Post-RP statin use remained significantly associated with decreased BCR risk after adjusting for preoperative serum cholesterol levels. When the investigators stratified findings by race, they noted that post-operative statin use was associated with a significant 51% decreased risk of BCR among non-black patients and a non-significant 18% lower risk among blacks, the researchers

014_RUN0714_News.indd 14

reported online ahead of print in BJU International.

“There may be a variety of explanations for this, including racial differences in prostate cancer biology, potential differences in medication adherence between races, and relatively small numbers of

Researchers find a significant reduction in BCR risk among non-black patients. black men in this study,” Dr. Allott told Renal & Urology News. “Given that this study is the first evidence of a possible race-specific effect of statins on prostate cancer progression, this finding requires further testing in future studies.”

Of the 1,146 patients, 400 (35%) used statins after RP and before BCR. The

investigators defined BCR as a single PSA value greater than 0.2 ng/mL, 2 consecutive levels at 0.2 ng/mL, or a secondary treatment for detectable postoperative PSA. Overall, compared with patients who did not use statins after RP, those who did had significantly lower median preoperative PSA levels (5.9 vs. 7.1 ng/mL), higher median body mass index (27.6 vs. 27.1 kg/m2), lower biopsy and pathologic Gleason scores, fewer positive margin (40% vs. 50%), and less seminal vesicle invasion (5% vs.

11%). Additionally, post-RP statin users had higher median serum cholesterol before surgery (202 vs. 185 mg/dL).

Previously, Robert J. Hamilton, MD, MPH, of Duke University School of Medicine, and collaborators reported in Cancer (2010;116:3389-3398) that preoperative statin use was associated with a significant 30% decreased risk of BCR after adjusting for multiple clinical and pathologic factors. The finding was

based on an analysis of data from 1,319 RP patients .

Other studies, however, have yielded conflicting findings. Researchers from Kaiser Permanente Southern California recently published a study of 1,200 PCa patients in BJU International (2013;111:954-962) showing no significant association between pre- or postoperative statin use and risk of BCR or clinical progression of disease following surgery.

Moreover, a retrospective study of 6,842 RP patients—of whom 2,275 (33.3%) were statin users—found no independent association between statin use and BCR risk, according to a paper published in Prostate Cancer and Prostatic Diseases (2013;16:367-371). A systematic review and meta-analysis published in the Annals of Oncology (2013;24:1427-1434) concluded that statins are associated with a significant improvement in recurrence-free survival among PCa patients who received radiotherapy, but not RP patients. n

6/20/14 12:38 PM

www.renalandurologynews.com JULY 2014

Renal & Urology News 15

Pre-Op ASA Score Predicts AKI Risk As the score increases, so does the likelihood of post-operative acute kidney injury, a study found

BY JILL STEIN AMSTERDAM—Pre-operative Amer­ i­can Society of Anesthesiology (ASA) physical status independently predicts the onset of post-operative acute kidney injury (AKI) in surgical patients, U.K. researchers reported at the 51st Congress of the European Renal Association-European Dialysis and Transplant Association.

Michael Bedford, MBBS, Renal Research Registrar at East Kent University Hospitals NHS Foundation in Canterbury, and his colleagues tested the ability of ASA score to predict AKI following surgery using data from general anesthetic operative procedures conducted with pre- and postoperative renal function testing. The procedures were performed over a recent 2-year period at three hospitals in the U.K.

Uric Acid May Predict Outcomes AMSTERDAM—Serum uric acid (UA) levels may be a clinically useful nutritional marker and outcome predictor in patients on maintenance hemodialysis (MHD), researchers reported at the European Renal AssociationEuropean Dialysis and Transplant Association annual congress.

Ilia Beberashvili, MD, of Assaf Harofeh Medical Center in Zerifin, Israel, and colleagues presented evidence that SUA is associated with most surrogates of body composition, muscle function, inflammation, and healthrelated quality of life in MHD patients.

The evidence comes from a 2-year prospective observational study that included 261 MHD patients with a mean age of 68.6 years. UA correlated positively with laboratory nutritional markers (albumin and creatinine) as well as body composition parameters (hand-grip strength), and geriatric nutritional risk index. UA correlated negatively with malnutrition-inflammation score and interleukin-6, an inflammatory marker.

In addition, patients in the highest quartile of UA had significantly higher total Short Form-36 (SF-36) scores and

015_RUN0714.indd 15

Although traditional risk factors such as age, diabetes, heart disease are important in gauging AKI risk, the investigators had believed that co-morbidity may not fully reflect functional status.

Developed more than 50 years ago, the ASA score provides a subjective

Findings raise the possibility of using ASA score to stratify risk before surgery. assessment of a patient’s overall health that is based on a 5-category physical status classification system and is used to stratify patients prior to surgery.

In the study by Dr. Bedford’s group, AKI developed post-operatively in

SF-36 physical functioning and physical role function scores.

Each 1 mg/dL increment in baseline UA level was associated with a 21% and 40% decreased likelihood of a first hospitalization and first cardiovascular (CV) event, respectively.

It also was associated with a 41% and 47% decreased likelihood of all-cause mortality and CV death, respectively, in adjusted analyses.

“UA is a simple, easily performed and inexpensive laboratory test that can be useful in conjunction with serum albumin in quickly identifying MHD patients with nutritional risks and those needing early nutritional interventions,” the authors concluded.

Some recently published studies have implicated high UA levels with adverse outcomes in patients with endstage renal disease. In a study of 880 kidney transplant recipients, researchers in Taiwan found that persistently high serum UA is associated with elevations in serum creatinine, which could increase the risk for allograft dysfunction, according to a paper published in Transplantation Proceedings (2014;46:505-510). In addition, in a study of 2,264 patients on peritoneal dialysis published in PLoS One (2014;9:e82342), Chinese investigators demonstrated that each 1 mg/dL increment in UA was associated with a 5% and 12% increase in the risk of all-cause and cardiovascular mortality, respectively. n

5.8%, 9.2%, 15.1%, 22.0%, 45.4% of patients with an ASA score of 1, 2, 3, 4, and 5, respectively.

ASA score was independently associated with the development of AKI postoperatively. Compared with a patient who had an ASA score of 1, those with an ASA score of 3, 4, and 5 were at 1.5, 2.0, and 3.7 times increased risk of postoperative AKI. “This study demonstrates that ASA status pre-operatively is an important predictor of developing AKI post-operatively in an unselected general hospital population,” the researchers concluded in their study abstract. “This raises the possibility of using ASA to stratify risk and direct interventions pre-operatively to ultimately prevent AKI.” Dr. Bedford’s group also noted that their results “show the superiority of functional status over the presence of

co-morbidity in risk stratification.”

The study is not the first to show that ASA physical status is associated with post-operative AKI risk. In a study published in Critical Care (2009;13:R79), Fernando José Abelha, MD, of Hospital de São João, in Porto, Portugal, and colleagues found that a high ASA score was independently associated with a nearly 4-fold increased risk of developing AKI. The study population included 1,166 patients with no previous renal insufficiency admitted to an intensive care unit. Of these, 87 (7.5%) met AKI criteria. Results showed that 22% of the AKI patients had ASA scores of 4 or 5 compared with 5% of those without AKI. Patients with AKI were significantly older than those without AKI (median 68 vs. 64 years) and had significantly lower body mass index (median 24 vs. 25 kg/m2). n

SWL Found to Have Minimal Impact on Renal Function ORLANDO, Fla.—Even multiple shock

treatments (82.7 vs. 84.9 vs. 81.8 mL/

wave lithotripsy (SWL) treatments have

min/1.73 m2). In multivariate analysis,

negligible impact on global renal func-

age was the only predictor of final

tion, Canadian researchers reported

eGFR. Additionally, results showed no

at the American Urological Association

difference in change in eGFR among

2014 annual meeting.

patients treated with a single SWL

Stephanie Tam, MD, and col-

treatment compared with those who

laborators at the University of Toronto

had multiple treatments. While CKD

retrospectively analyzed data from 324

class deteriorated in 8.7% of patients,

patients who underwent at least 1 SWL

it improved in 4.3%, and the number of

treatment and 2 or more 24-hour urine

SWL treatments did not impact change

collections at Toronto’s St. Michael’s

in CKD class.

Hospital from 2002–2013. The inves-

“There has been a growing body

tigators divided patients into 3 groups

of evidence that stone formers are

based on the number of SWL treat-

at a higher risk of developing kidney

ments. 1, 2–5, and more than 5. As a

disease in the long run, and there have

marker of renal function, they used esti-

been some animal studies to suggest

mated glomerular filtration rate (eGFR)

that shock wave lithotripsy may result

as calculated using the Modification of

in renal fibrosis, which could obviously

Diet in Renal Disease study equation.

impact renal function down the road,”

Of the 324 patients, 90% had normal

said Dr. Tam, a urology fellow. “Overall,

renal function or mild chronic kidney

there was a slight decrease in renal

disease (CKD) at baseline. Forty-four

function after shock wave [lithotripsy],

had 1 SWL treatment, 227 had 2–5

but when we looked at it based on the

treatments, and 44 had more than 5

number of treatments the patients

treatments. The researchers found no

received, there was no correlation

significant difference in baseline renal

between shock waves and deteriora-

function in patients requiring more

tion of renal function.” n

6/20/14 12:45 PM

20 Renal & Urology News

JULY 2014 www.renalandurologynews.com

Autologous Immunotherapy for mRCC Shows Promise AN INVESTIGATIONAL autologous immunotherapy used in combination with sunitinib significantly improved long-term survival in patients with unfavorable-risk metastatic renal cell carcinoma (mRCC), researchers reported at the American Society of Clinical Oncology annual meeting in Chicago.

In a phase 2 study of 21 subjects who received the dual regimen, investigators Asim Amin, MD, PhD, of the Levine Cancer Institute in Charlotte, N.C., and colleagues observed a doubling of the expected median progression-

Thyroid Problems Up Cardiac Risks SUBCLINICAL hyperthyroidism and euthyroid sick syndrome may increase the risk of sudden cardiac death

free survival (PFS) and overall survival (OS), with 52% of patients surviving more than 30 months and 23% surviving for more than 5 years. The patients received 5 doses of the immunotherapy spaced 3 weeks apart.

For all patients, the time from diagnosis to the initiation of treatment was

less than 1 year. The expected median PFS and OS in these patients, based on an analysis by the International mRCC Database Consortium, are 5.6 and 14.7 months, respectively.

The autologous immunotherapy, B:7.25 in AGS-003, provides 3 signals required to T:7 in generate an adaptive immune response, S:6.5 in

the researchers explained in a poster presentation. These signals stimulate production of effector memory cytotoxic T lymphocytes.

The memory T-cell response observed after 5 doses of AGS-003 correlates with prolonged survival, Dr. Amin’s group reported. n

In a clinical trial of men with mCRPC who progressed on ADT*…

More than 1,000 days.

And each writes its own story.

35.3 5.2

MONTHS MEDIAN OVERALL SURVIVAL FOR ZYTIGA® (abiraterone acetate) PLUS PREDNISONE† vs 30.1 months with placebo plus prednisone (active compound).‡ MONTHS IMPROVEMENT IN MEDIAN OVERALL SURVIVAL compared with placebo plus prednisone (active compound).

among diabetic hemodialysis (HD) patients, a prospective study found.

The study, by Christiane Drechsler, MD, PhD, of University Hospital Würzburg, Würzburg, Germany, and colleagues included 1,000 diabetic HD patients, of whom 78.1% had euthyroidism, 13.7% had subclinical hypothyroidism, and 5.4% had euthy-

T:10 in

S:9.5 in

hyperthyroidism, 1.6% had subclinical roid sick syndrome. Compared with patients who had euthyroidism, those who had subclinical hyperthyroidism and euthyroid sick syndrome had a 2.0 times and 2.7 times increased shortterm (within 12 months) risk of sudden cardiac death, respectively, according to a report in the American Journal of Kidney Diseases (2014;63:988996). Results showed that euthyroid sick syndrome was associated with a 3-fold increased risk of short-term mortality, but no increased risk in the long term (2–4 years). Subclinical hypothyroidism was not associated with cardiovascular events or all-cause mortality. Thyroid disorders had no meaningful effect on the risks of myocardial infarction and stroke.

“Regular assessment of thyroid status may help estimate the cardiac risk of dialysis patients,” the

INDICATION ZYTIGA® (abiraterone acetate) in combination with prednisone is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC).

IMPORTANT SAFETY INFORMATION Contraindications—ZYTIGA® is not indicated for use in women. ZYTIGA® can cause fetal harm (Pregnancy Category X) when administered to a pregnant woman and is contraindicated in women who are or may become pregnant.

Adverse Reactions—The most common adverse reactions (≥10%) are fatigue, joint swelling or discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection, and contusion.

The most common laboratory abnormalities (>20%) are anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, elevated AST, hypophosphatemia, elevated ALT, and hypokalemia.

Increased ZYTIGA® Exposures With Food—ZYTIGA® must be taken on an empty stomach. 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 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. *Study Design: ZYTIGA®, in combination with prednisone, was evaluated in a phase 3, randomized, double-blind, placebo-controlled, multicenter trial in patients with mCRPC who had not received prior chemotherapy (N=1,088). Patients were using a luteinizing hormone-releasing hormone (LHRH) agonist or were previously treated with orchiectomy. In the ZYTIGA® arm, patients received ZYTIGA® 1,000 mg orally once daily + prednisone 5 mg orally twice daily. In the placebo arm, patients received placebo orally once daily + prednisone 5 mg orally twice daily. In this study, the coprimary efficacy end points were overall survival (OS) and radiographic progression-free survival. †Coprimary end point: hazard ratio=0.792; 95% CI: 0.655, 0.956; P=0.0151; prespecified value for statistical significance not reached. At a prespecified interim analysis for OS, 37% (200/546) of patients treated with ZYTIGA® plus prednisone compared with 43% (234/542) of patients treated with placebo plus prednisone had died. ‡Prednisone, as a single agent, is not approved for the treatment of prostate cancer.

H w pr co in C C po A af an st pa m

mC

Pl o Pl o

researchers concluded. n

020_RUN0714_news_A.indd 20

Date: 06/10/14

Customer Code: 014686-140502

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Renal & Urology News 21

Metformin Use Decreases Risk of PCa Diagnosis USE OF the diabetes drug metformin may be associated with a decreased risk of a prostate cancer (PCa) diagnosis.

In a study of 12,226 men diagnosed with PCa and 122,260 population controls, Mark A. Preston, MD, of Massachusetts General Hospital in Boston, and colleagues found that men

who used metformin had a significant 16% decreased risk of a PCa diagnosis in adjusted analyses compared with nonusers. Among men who had undergone PSA testing in the previous year, metformin use was associated with a significant B:7.25 in 34% decreased risk of a PCa diagnosis.

T:7 in Diabetics on no medication or on other S:6.5 in

oral hypoglycemic agents did not have a significant decrease in the risk of a PCa diagnosis, the researchers reported online ahead of print in European Urology.

The researchers identified study subjects using the Danish Cancer Registry and the Aarhus University Prescription Database.

In a previous Canadian study of older diabetic men published in the Journal of the National Cancer Institute (2013;105:1123-1131), researchers found no association between metformin use and PCa risk. The study included 5,306 PCa case subjects and 26,530 matched controls. n

.‡

T:10 in

B:10.25 in

S:9.5 in

T:10 in

B:10.25 in

S:9.5 in

d.

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 blood pressure, hypokalemia, or 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 (in Study 1) or NYHA Class II to IV heart failure (in Study 2) because these patients were excluded from these randomized clinical trials.

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 was reported 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. mCRPC=metastatic castration-resistant prostate cancer; ADT=androgen-deprivation therapy.

Please see additional Important Safety Information on the next page.

Please see brief summary of full Prescribing Information on subsequent pages.

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ADT May Be Safely Deferred After PSA Relapse IMMEDIATE ANDROGEN deprivation therapy (ADT) offers little or no survival benefit over deferred ADT to prostate cancer patients who experience PSA-only relapse after primary treatment, researchers concluded in a presentation at the American Society of Clinical Oncology annual meeting in Chicago.

Xabier Garcia-Albeniz, MD, of Harvard School of Public Health, Boston, and colleagues studied 2,022 men who underwent radical prostatectomy or radiotherapy and experienced PSA-only relapse. Subjects had a median age of 69 years, and 33.8% had a Gleason score greater than 7. Dr.

Garcia-Albeniz and colleagues defined immediate ADT as ADT started within 3 months after PSA relapse and deferred ADT as ADT started 2 or more years after patients experienced PSA relapse or when they presented B:7.25 in with metastasis, symptoms, or a short T:7 in PSA doubling time.

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Compared with deferred ADT, immediate ADT was associated with a 6% increased risk of all-cause mortality and a 48% increased risk of prostate cancer-specific mortality, which corresponded to a - 5.5% and - 5.6% survival difference at 5 years, respectively., according to the investigators. n

For more information, please visit

www.zytigahcp.com.

003307-130924

Please see brief summary of full Prescribing Information on adjacent pages.

Janssen Biotech, Inc. © Janssen Biotech, Inc. 2014 5/14 014686-140502

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IMPORTANT SAFETY INFORMATION (cont) Hepatotoxicity—Monitor liver function and modify, withhold, or discontinue ZYTIGA® (abiraterone acetate) 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.

Drug Interactions—Based on in vitro data, ZYTIGA® is a substrate of CYP3A4. In a drug interaction trial, co-administration of rifampin, a strong CYP3A4 inducer, decreased exposure of abiraterone by 55%. Avoid concomitant strong CYP3A4 inducers during ZYTIGA® treatment. If a strong CYP3A4 inducer must be co-administered, increase the ZYTIGA® dosing frequency only during the co-administration period [see Dosage and Administration (2.3)]. In a dedicated drug interaction trial, co-administration of ketoconazole, a strong inhibitor of CYP3A4, had no clinically meaningful effect on the pharmacokinetics of abiraterone.

ZYTIGA® is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. Avoid co-administration with CYP2D6 substrates with a narrow therapeutic index. If alternative treatments cannot be used, exercise caution and consider a dose reduction of the CYP2D6 substrate drug. In vitro, ZYTIGA® inhibits CYP2C8. There are no clinical data on the use of ZYTIGA® with drugs that are substrates of CYP2C8. Patients should be monitored closely for signs of toxicity related to the CYP2C8 substrate if used concomitantly with abiraterone acetate.

Use in Specific Populations—Do not use ZYTIGA® in patients with baseline severe hepatic impairment (Child-Pugh Class C).

www.renalandurologynews.com JULY 2014

Fracture Risk Varies by Renal Replacement Therapy AMSTERDAM—Hemodialysis (HD) patients are at higher risk of fractures than renal transplant recipients and patients on peritoneal dialysis (PD), investigators reported at the 51st Congress of the European Renal Association-European Dialysis and Transplant Association.

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Vishal Dey, of University Hospital Crosshouse, Kilmarnock, U.K., and colleagues studied 2,096 patients on renal replacement therapy (RRT) in western Scotland. Of these, 1,081 (51.6%) were kidney transplant recipients, 907 (43.3%) were HD patients, and 108 (5.2%) were PD patients. The median

ZYTIGA® (abiraterone acetate) Tablets Brief Summary of Prescribing Information.

INDICATIONS AND USAGE ZYTIGA is a CYP17 inhibitor indicated in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer.

CONTRAINDICATIONS Pregnancy: ZYTIGA can cause fetal harm when administered to a pregnant woman. ZYTIGA is not indicated for use in women. 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, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss [see Use in Specific Populations].

WARNINGS AND PRECAUTIONS Hypertension, Hypokalemia and Fluid Retention Due to Mineralocorticoid Excess: ZYTIGA may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition [see Clinical Pharmacology (12.1) in full Prescribing Information].

In the two randomized clinical trials, grade 3 to 4 hypertension occurred in 2% of patients, grade 3 to 4 hypokalemia in 4% of patients, and grade 3 to 4 edema in 1% of patients treated with ZYTIGA [see Adverse Reactions].

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. Use ZYTIGA with caution in patients with a history of cardiovascular disease. The safety of ZYTIGA in patients with left ventricular ejection fraction <50% or New York Heart Association (NYHA) Class III or IV heart failure (in Study 1) or NYHA Class II to IV heart failure (in Study 2) was not established because these patients were excluded from these randomized clinical trials [see Clinical Studies (14) in full Prescribing Information]. 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: Adrenal insufficiency occurred in the two randomized clinical studies in 0.5% of patients taking ZYTIGA and in 0.2% of patients taking placebo. Adrenocortical insufficiency was reported 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: In the two randomized clinical trials, grade 3 or 4 ALT or AST increases (at least 5X ULN) were reported in 4% of patients who received ZYTIGA, typically during the first 3 months after starting treatment. Patients whose baseline ALT or AST were elevated were more likely to experience liver test elevation than those beginning with normal values. Treatment discontinuation due to liver enzyme increases occurred in 1% of patients taking ZYTIGA. No deaths clearly related to ZYTIGA were reported due to hepatotoxicity events.

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.

Increased ZYTIGA Exposures with Food: 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 17and 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].

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duration of follow-up was 1,112, 1,086, and 1,126 days, respectively.

A total of 337 fractures occurred in the study population, for an overall incidence of 0.062 fractures per patient year. Compared with the kidney transplant and PD groups, the risk of fracture in the HD group

was 2.6 times and 1.7 times greater, respectively.

“Further research is warranted to determine if the association between RRT modality and fracture incidence is independent of other risk factors for fracture,” the authors concluded in their study abstract. n

ZYTIGA® (abiraterone acetate) Tablets 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].

• Increased ZYTIGA Exposures with Food [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.

Two randomized placebo-controlled, multicenter clinical trials enrolled patients who had metastatic castration-resistant prostate cancer who were using a gonadotropin-releasing hormone (GnRH) agonist or were previously treated with orchiectomy. In both Study 1 and Study 2 ZYTIGA was administered at a dose of 1,000 mg daily in combination with prednisone 5 mg twice daily in the active treatment arms. Placebo plus prednisone 5 mg twice daily was given to control patients.

The most common adverse drug reactions (≥10%) reported in the two randomized clinical trials that occurred more commonly (>2%) in the abiraterone acetate arm were fatigue, joint swelling or discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection and contusion.

The most common laboratory abnormalities (>20%) reported in the two randomized clinical trials that occurred more commonly (≥2%) in the abiraterone acetate arm were anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, elevated AST, hypophosphatemia, elevated ALT and hypokalemia.

Study 1: Metastatic CRPC Following Chemotherapy: Study 1 enrolled 1195 patients with metastatic CRPC who had received prior docetaxel chemotherapy. Patients were not eligible if AST and/or ALT ≥2.5X ULN in the absence of liver metastases. Patients with liver metastases were excluded if AST and/or ALT >5X ULN. Table 1 shows adverse reactions on the ZYTIGA arm in Study 1 that occurred with a ≥2% absolute increase in frequency compared to placebo or were events of special interest. The median duration of treatment with ZYTIGA was 8 months.

Table 1: Adverse Reactions due to ZYTIGA in Study 1 ZYTIGA with Placebo with Prednisone (N=791) Prednisone (N=394) System/Organ Class All Grades1 Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % Musculoskeletal and connective tissue disorders Joint swelling/ discomfort2 29.5 4.2 23.4 4.1 Muscle discomfort3 26.2 3.0 23.1 2.3 General disorders 4 Edema 26.7 1.9 18.3 0.8 Vascular disorders Hot flush 19.0 0.3 16.8 0.3 Hypertension 8.5 1.3 6.9 0.3 Gastrointestinal disorders Diarrhea 17.6 0.6 13.5 1.3 Dyspepsia 6.1 0 3.3 0 Infections and infestations Urinary tract infection 11.5 2.1 7.1 0.5 Upper respiratory tract infection 5.4 0 2.5 0 Respiratory, thoracic and mediastinal disorders Cough 10.6 0 7.6 0 Renal and urinary disorders Urinary frequency 7.2 0.3 5.1 0.3 Nocturia 6.2 0 4.1 0 Injury, poisoning and procedural complications Fractures5 5.9 1.4 2.3 0 Cardiac disorders Arrhythmia6 7.2 1.1 4.6 1.0 Chest pain or chest 7 discomfort 3.8 0.5 2.8 0 Cardiac failure8 2.3 1.9 1.0 0.3

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Pre-Existing HTN Benefits Sunitinib Recipients PRE-EXISTING hypertension (HTN) predicts improved overall and progression-free survival in patients with metastatic renal cell carcinoma (mRCC) treated with sunitinib, according to a French study presented at the American Society of Clinical Oncology annual meeting in Chicago.

The study, led by Bernard Escudier, MD, of Institut Gustave Roussy in Villejuif, included 213 mRCC patients treated with the VEGF inhibitor sunitinib. Patients had a median age of 59 years and median follow-up of 43 months. Eighty-eight patients (41%) had pre-existing HTN, including 58

(66%) receiving angiotensin receptor blockers or some other angiotensin system inhibitor. Overall survival (OS) and progression-free survival (PFS) were significantly longer among the patients with pre-existing HTN than among those without it (33 vs. 23 months and 12 vs. 9 months, respectively).

ZYTIGA® (abiraterone acetate) Tablets

ZYTIGA® (abiraterone acetate) Tablets

1 Adverse events graded according to CTCAE version 3.0 2 Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness 3 Includes terms Muscle spasms, Musculoskeletal pain, Myalgia,

Table 3: Adverse Reactions in ≥5% of Patients on the ZYTIGA Arm in Study 2 (continued) ZYTIGA with Placebo with Prednisone (N=542) Prednisone (N=540) 1 System/Organ Class All Grades Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % Renal and urinary disorders Hematuria 10.3 1.3 5.6 0.6 Skin and subcutaneous tissue disorders Rash 8.1 0.0 3.7 0.0 1 Adverse events graded according to CTCAE version 3.0 2 Includes terms Edema peripheral, Pitting edema, and Generalized edema 3 Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness

Musculoskeletal discomfort, and Musculoskeletal stiffness terms Edema, Edema peripheral, Pitting edema, and Generalized edema 5 Includes all fractures with the exception of pathological fracture 6 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 4 Includes

Table 2 shows laboratory abnormalities of interest from Study 1. Grade 3-4 low serum phosphorus (7%) and low potassium (5%) occurred at a greater than or equal to 5% rate in the ZYTIGA arm.

Table 2: Laboratory Abnormalities of Interest in Study 1 Abiraterone (N=791) Placebo (N=394) Laboratory All Grades Grade 3-4 All Grades Grade 3-4 Abnormality (%) (%) (%) (%) Hypertriglyceridemia 62.5 0.4 53.0 0 High AST 30.6 2.1 36.3 1.5 Hypokalemia 28.3 5.3 19.8 1.0 Hypophosphatemia 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 Study 2: Metastatic CRPC Prior to Chemotherapy: Study 2 enrolled 1088 patients with metastatic CRPC who had not received prior cytotoxic chemotherapy. Patients were ineligible if AST and/or ALT ≥2.5X ULN and patients were excluded if they had liver metastases.

Table 3 shows adverse reactions on the ZYTIGA arm in Study 2 that occurred with a ≥2% absolute increase in frequency compared to placebo.

The median duration of treatment with ZYTIGA was 13.8 months.

Table 3: Adverse Reactions in ≥5% of Patients on the ZYTIGA Arm in Study 2 ZYTIGA with Placebo with Prednisone (N=542) Prednisone (N=540) System/Organ Class All Grades1 Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % General disorders Fatigue 39.1 2.2 34.3 1.7 Edema2 25.1 0.4 20.7 1.1 Pyrexia 8.7 0.6 5.9 0.2 Musculoskeletal and connective tissue disorders Joint swelling/ discomfort3 30.3 2.0 25.2 2.0 Groin pain 6.6 0.4 4.1 0.7 Gastrointestinal disorders Constipation 23.1 0.4 19.1 0.6 Diarrhea 21.6 0.9 17.8 0.9 Dyspepsia 11.1 0.0 5.0 0.2 Vascular disorders Hot flush 22.3 0.2 18.1 0.0 Hypertension 21.6 3.9 13.1 3.0 Respiratory, thoracic and mediastinal disorders Cough 17.3 0.0 13.5 0.2 Dyspnea 11.8 2.4 9.6 0.9 Psychiatric disorders Insomnia 13.5 0.2 11.3 0.0 Injury, poisoning and procedural complications Contusion 13.3 0.0 9.1 0.0 Falls 5.9 0.0 3.3 0.0 Infections and infestations Upper respiratory tract infection 12.7 0.0 8.0 0.0 Nasopharyngitis 10.7 0.0 8.1 0.0

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Among the patients with pre-existing HTN, those receiving treatment with angiotensin system inhibitors had significantly better OS, but not PFS, than subjects not treated with these medications.

HTN is one of the most frequent adverse effects of VEGF inhibitors, the researchers noted. n

Table 4 shows laboratory abnormalities that occurred in greater than 15% of patients, and more frequently (>5%) in the ZYTIGA arm compared to placebo in Study 2. Grade 3-4 lymphopenia (9%), hyperglycemia (7%) and high alanine aminotransferase (6%) occurred at a greater than 5% rate in the ZYTIGA arm.

Table 4: Laboratory Abnormalities in >15% of Patients in the ZYTIGA Arm of Study 2 Abiraterone (N=542) Placebo (N=540) Laboratory Grade 1-4 Grade 3-4 Grade 1-4 Grade 3-4 Abnormality % % % % Hematology Lymphopenia 38.2 8.7 31.7 7.4 Chemistry Hyperglycemia1 56.6 6.5 50.9 5.2 High ALT 41.9 6.1 29.1 0.7 High AST 37.3 3.1 28.7 1.1 Hypernatremia 32.8 0.4 25.0 0.2 Hypokalemia 17.2 2.8 10.2 1.7 1Based on non-fasting blood draws Cardiovascular Adverse Reactions: In the combined data for studies 1 and 2, cardiac failure occurred more commonly in patients treated with ZYTIGA compared to patients on the placebo arm (2.1% versus 0.7%).

Grade 3-4 cardiac failure occurred in 1.6% of patients taking ZYTIGA and led to 5 treatment discontinuations and 2 deaths. Grade 3-4 cardiac failure occurred in 0.2% of patients taking placebo. There were no treatment discontinuations and one death due to cardiac failure in the placebo group.

In Study 1 and 2, the majority of arrhythmias were grade 1 or 2. There was one death associated with arrhythmia and one patient with sudden death in the ZYTIGA arms and no deaths in the placebo arms. There were 7 (0.5%) deaths due to cardiorespiratory arrest in the ZYTIGA arms and 3 (0.3%) deaths in the placebo arms. Myocardial ischemia or myocardial infarction led to death in 3 patients in the placebo arms and 2 deaths in the ZYTIGA arms.

Post Marketing Experience The following additional adverse reactions have been identified during post approval use of ZYTIGA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Respiratory, Thoracic and Mediastinal Disorders: non-infectious pneumonitis.

DRUG INTERACTIONS Drugs that Inhibit or Induce CYP3A4 Enzymes: Based on in vitro data, ZYTIGA is a substrate of CYP3A4.

In a dedicated drug interaction trial, co-administration of rifampin, a strong CYP3A4 inducer, decreased exposure of abiraterone by 55%. Avoid concomitant strong CYP3A4 inducers during ZYTIGA treatment. If a strong CYP3A4 inducer must be co-administered, increase the ZYTIGA dosing frequency [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3) in full Prescribing Information].

In a dedicated drug interaction trial, co-administration of ketoconazole, a strong inhibitor of CYP3A4, had no clinically meaningful effect on the pharmacokinetics of abiraterone [see Clinical Pharmacology (12.3) in full Prescribing Information].

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

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Tumor Size Predicts Biochemical Recurrence Risk ORLANDO, Fla.—Maximal tumor diameter (MTD) may predict which prostate cancer patients are at very low risk of PSA failure following radical prostatectomy who may not benefit from adjuvant radiation therapy.

In a study, MTD identified patients at low risk of PSA failure even in the

presence of adverse features such as a high Gleason score of extracapsular extension, which are associated with a high risk of PSA failure, according to investigator Brent S. Rose, MD, a radiation oncology resident in the Harvard Radiation Oncology Program in Boston. He presented study findings

at the American Urological Association 2014 annual meeting.

Dr. Rose and colleagues studied 354 men with T1c-T2 PCa who underwent radical prostatectomy without adjuvant therapy. The MTD was defined as the maximal linear dimension of the largest single focus of tumor. After a median fol-

ZYTIGA® (abiraterone acetate) Tablets

ZYTIGA® (abiraterone acetate) Tablets

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 inhibits CYP2C8. There are no clinical data on the use of ZYTIGA with drugs that are substrates of CYP2C8. However, patients should be monitored closely for signs of toxicity related to the CYP2C8 substrate if used concomitantly with abiraterone acetate.

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 Human experience of overdose with ZYTIGA is limited.

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 in the range from 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].

PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information) • Patients should be informed that ZYTIGA and prednisone are used together and that they should not interrupt or stop either of these medications without consulting their physician.

• Patients receiving GnRH agonists should be informed that they need to maintain this treatment during the course of treatment with ZYTIGA and prednisone.

• Patients should be informed that ZYTIGA must not be taken with food and that 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. They should be informed that the tablets should be swallowed whole with water without crushing or chewing. Patients should be informed that taking ZYTIGA with food causes increased exposure and this may result in adverse reactions.

• Patients should be informed that ZYTIGA is taken once daily and prednisone is taken twice daily according to their physician’s instructions.

• Patients should be informed that in the event of a missed daily dose of ZYTIGA or prednisone, they should take their normal dose the following day. If more than one daily dose is skipped, patients should be told to inform their physician.

• Patients should be apprised of the common side effects associated with ZYTIGA, including peripheral edema, hypokalemia, hypertension, elevated liver function tests, and urinary tract infection. Direct the patient to a complete list of adverse drug reactions in PATIENT INFORMATION. • Patients should be advised that their liver function will be monitored using blood tests.

• Patients should be informed that ZYTIGA may harm a developing fetus; thus, women who are pregnant or women who may be pregnant should not handle ZYTIGA without protection, e.g., gloves. Patients should also be informed that it is not known whether abiraterone or its metabolites are present in semen and they should use a condom if having sex with a pregnant woman. The patient should use a condom and another effective method of birth control if he is having sex with a woman of child-bearing potential. These measures are required during and for one week after treatment with ZYTIGA.

USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category X [see Contraindications].: ZYTIGA can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. While there are no adequate and well-controlled studies with ZYTIGA in pregnant women and ZYTIGA is not indicated for use in women, it is important to know that maternal use of a CYP17 inhibitor could affect development of the fetus. Abiraterone acetate caused developmental toxicity in pregnant rats at exposures that were lower than in patients receiving the recommended dose. 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, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss. Advise females of reproductive potential to avoid becoming pregnant during treatment with ZYTIGA. In an embryo-fetal developmental toxicity study in rats, abiraterone acetate caused developmental toxicity when administered at oral doses of 10, 30 or 100 mg/kg/day throughout the period of organogenesis (gestational days 6-17). Findings included embryo-fetal lethality (increased post implantation loss and resorptions and decreased number of live fetuses), fetal developmental delay (skeletal effects) and urogenital effects (bilateral ureter dilation) at doses ≥10 mg/kg/day, decreased fetal ano-genital distance at ≥30 mg/kg/day, and decreased fetal body weight at 100 mg/kg/day. Doses ≥10 mg/kg/day caused maternal toxicity. The doses tested in rats resulted in systemic exposures (AUC) approximately 0.03, 0.1 and 0.3 times, respectively, the AUC in patients.

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: Safety and effectiveness of ZYTIGA in pediatric patients have not been established.

Geriatric Use: Of the total number of patients receiving ZYTIGA in phase 3 trials, 73% of patients were 65 years and over and 30% were 75 years and over. No overall differences in safety or effectiveness were observed between these elderly patients and younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

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.

In another trial, the pharmacokinetics of abiraterone were examined in subjects with baseline severe (n=8) hepatic impairment (Child-Pugh Class C) and in 8 healthy control subjects with normal hepatic function. The systemic exposure (AUC) of abiraterone increased by approximately 7-fold and the fraction of free drug increased 2-fold in subjects with severe baseline hepatic impairment 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 (ChildPugh Class B), reduce the recommended dose of ZYTIGA to 250 mg once daily. Do not use ZYTIGA in patients with baseline severe hepatic impairment (Child-Pugh Class C). 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].

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.

Manufactured by: Patheon Inc. Mississauga, Canada Manufactured for: Janssen Biotech, Inc. Horsham, PA 19044 © Janssen Biotech, Inc. 2012 Revised: May 2014 015924-140528

low-up of 4.0 years, 34 men (9.6%) experienced PSA relapse. On multivariable analysis, increasing MTD, PSA, pathologic Gleason score, T stage, and positive surgical margins were significantly associated with an increased PSA failure risk.

Among men with a pre-RP PSA level above 4 ng/mL—but not in those with a PSA of 4 ng/mL or less—the 5-year estimated PSA failure-free survival rate was significantly lower in patients whose MTD was larger than 1.2 cm (the median MTD for the entire cohort) compared with those with an MTD of 1.2 cm or smaller (74.5% vs. 99.0%). If a patient had at least 1 adverse feature, such as pT3 disease or a Gleason score of 8 or higher, the 5-year estimated PSA failurefree survival rates were 46.6% and 100% for men whose MTD was larger than 1.2 cm and 1.2 cm or smaller, respectively. n

Smoking Ups Stroke Risk in HD Patients AMSTERDAM—Smoking and diabetes are among the risk factors for ischemic stroke in hemodialysis (HD) patients, researchers reported at the 51st Congress of the European Renal Association-European Dialysis and Transplant Association.

Camilla Nilssen, MD, of Oslo University Hospital in Norway, and colleagues studied 2,773 HD patients who had a median age of 64 years at baseline. The mean time on dialysis at study inclusion was 3.5 years. During a median follow-up of 3.8 years, 105 stroke events (ischemic cerebral stroke and death from ischemic stroke) occurred. Current smoking and diabetes were associated with a significant 2.1 times and 1.72 times increased risk of ischemic cerebral stroke, respectively. Increasing age and dialysis vintage were associated with an increasing risk of ischemic cerebral stroke, whereas increasing albumin level was associated with a decreasing risk. The study revealed no association between ischemic cerebral stroke and gender, systolic blood pressure, phosphate, body mass index, and LDL-cholesterol. n

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