Renal & Urology News - Jan-Feb 2018 issue

J A N U A R Y/F E B R U A R Y 2 018

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V O L U M E 17, I S S U E N U M B E R 1

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RC Tied to Better Survival in MIBC

IN THIS ISSUE 9

Study identifies predictors of RCC bone metastasis

25 New genetic testing guidelines issued for prostate cancer 26 Prostate cancer grade group system gains wide acceptance

28 Pros and cons of outpatient

transperineal prostate biopsy

31 Urologic cancer risk is higher among ESRD patients

Novel 3D printing method creates prostate models that closely mimic the real gland.

PAGE 15

onward, CRT was associated with a significant 40% and 50% increased mortality risk, respectively, Chad R. Ritch, MD, and collaborators at the University of Miami Miller School of Medicine reported online ahead of print in BJU International.

The median overall survival (OS) was significantly lower among CRT recipients compared with those who underwent RC (30% vs 38%). OS was lower with RC versus CRT until about 16 months, “at which point there was a significant monthly increase in the likelihood of death following CRT

© PHOTO CREDIT

BY JODY A. CHARNOW RADICAL CYSTECTOMY may offer superior long-term survival compared with chemoradiation therapy for patients with muscle-invasive bladder cancer (MIBC) who are suitable surgical candidates and have a low risk of morbidity, researchers concluded.

In an analysis of a propensity matched cohort of MIBC patients, chemoradiation therapy (CRT) was associated with a significant 16% lower mortality risk at 1-year post-treatment compared with radical cystectomy (RC), the standard of care for MIBC, but at year 2 and year 3

RADICAL CYSTECTOMY for muscle-invasive bladder cancer may offer better long-term survival.

c­ompared with RC that continued throughout the follow up period.”

The investigators concluded that their findings “suggest that RC may be beneficial in those patients who are suitable surgical candidates with a long life expectancy, compared to CRT. In

c­ ontrast, patients who are high-risk surgical candidates may be better served

by CRT given the decreased OS associated with RC in the first 16 months.”

The overall study population, identified using the National Cancer Database continued on page 12

Researchers Link Early RRT for AKI Not Better High Cholesterol, EARLY INITIATION of renal replace- the 592 patients (48.8%) who received therapy (RRT) for acute kidney late RRT (RRT initiation at AKI stage High-grade PCa ment injury (AKI) in intensive care unit 3). Early RRT was associated with a

BY JODY A. CHARNOW HIGH SERUM LEVELS of total and HDL cholesterol are associated with an elevated risk of high-grade prostate cancer (PCa), researchers concluded.

In a post-hoc analysis of data from 4974 non-statin-using men in the REDUCE (Reduction by Dutasteride of Prostate Cancer Events) trial, a team led by Stephen J. Freedland, MD, of Cedars-Sinai Medical Center in Los Angeles, found that each 10 mg/dL increase in serum total and HDL cholesterol is associated with a significant 5% and 14% increased odds of a diagnosis of high-grade PCa, respectively. continued on page 12

patients is associated with increased 90-day mortality compared with late RRT, but for patients surviving to day 90, both strategies are associated with similar long-term risks of mortality, chronic kidney disease, and end-stage renal disease, investigators reported online ahead of print in Critical Care .

In a cohort study of 1213 patients treated with continuous RRT, the 90-day mortality rate was 53.6% among the 621 patients (51.2%) who received early RRT (RRT initiation at AKI stage 2 or below) compared with 46% among

statistically significant 24% increased risk of 90-day mortality compared with late RRT, Søren Christiansen, MD, of Aarhus University Hospital in Aarhus N, Denmark, and colleagues reported.

The 90-day to 5-year mortality rates were 37.7% and 41.5% in the early and late RRT groups, respectively. The 5-year rates of chronic kidney disease (CKD) and end-stage renal disease (ESRD) were 35.9% and 13.3%, respectively, in the early RRT group and 44.9% and 16.7% in the late RRT group. None of continued on page 12

GLEASON GRADE Earn 1 CME creditGROUP in this issue SYSTEM USE EXPANDING

ItRelationships is now included of in pathology reports Testosterone andand patient Prostatecounseling.

Cancer PAGE26 00 PAGE

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Long-term death risk lower versus chemoradiation

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Upon progression on GnRH therapy* in mCRPC1

To reduce the risk of radiographic progression in metastatic CRPC†1 National Comprehensive Cancer Network® (NCCN®)2 The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) recommend enzalutamide (XTANDI) as a Category 1 first-line treatment option for patients with metastatic CRPC||2

83% reduction in the risk of radiographic progression or death

‡

with XTANDI + GnRH therapy* vs placebo + GnRH therapy*1 • HR = 0.17 (95% CI, 0.14-0.21); P < 0.0001 Overall survival, co-primary endpoint§: 23% reduction in risk of death with XTANDI + GnRH therapy* vs placebo + GnRH therapy* (HR = 0.77 [95% CI, 0.67-0.88])1

CI, confidence interval; GnRH therapy, gonadotropin-releasing hormone therapy; HR, hazard ratio; mCRPC, metastatic castration-resistant prostate cancer. *Or after bilateral orchiectomy.1 † As seen in the PREVAIL trial (Study 2): a multinational, double-blind, randomized, phase 3 trial that enrolled 1717 patients with metastatic CRPC who progressed on GnRH therapy or after bilateral orchiectomy, and who had not received prior cytotoxic chemotherapy. All patients continued on GnRH therapy.1,3 ‡ Radiographic progression was assessed by blinded Independent Central Review (ICR) per Prostate Cancer Clinical Trials Working Group 2 (PCWG2) criteria for bone lesion progression and/or Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) for soft tissue/visceral disease progression.1,3 § An updated survival analysis was conducted when 784 deaths were observed. The median follow-up time was 31 months. Results from this analysis were consistent with those from the prespecified interim analysis.1 II Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.2

Learn more about XTANDI at XtandiHCP.com

Important Safety Information Contraindications XTANDI is not indicated for women. XTANDI can cause fetal harm and potential loss of pregnancy.

Warnings and Precautions Seizure occurred in 0.5% of patients receiving XTANDI in clinical studies. In a study of patients with predisposing factors, seizures were reported in 2.2% of patients. See section 5.1 of the Prescribing Information for the list of predisposing factors. It is unknown whether anti-epileptic medications will prevent seizures with XTANDI. Permanently discontinue XTANDI in patients who develop a seizure during treatment.

Posterior Reversible Encephalopathy Syndrome (PRES) In post approval use, there have been reports of PRES in patients receiving XTANDI. PRES is a neurological disorder which can present with rapidly evolving symptoms including seizure, headache, lethargy, confusion, blindness, and other visual and neurological disturbances, with or without associated hypertension. A diagnosis of PRES requires confirmation by brain imaging, preferably MRI. Discontinue XTANDI in patients who develop PRES.

Adverse Reactions The most common adverse reactions (≥ 10%) that occurred more commonly (≥ 2% over placebo) in the XTANDI patients from

In the placebo-controlled study of patients taking XTANDI who previously received docetaxel, Grade 3 and higher adverse reactions were reported among 47% of XTANDI patients and 53% of placebo patients. Discontinuations due to adverse events were reported for 16% of XTANDI patients and 18% of placebo patients.

In the placebo-controlled study of chemotherapy-naïve patients, Grade 3-4 adverse reactions were reported in 44% of XTANDI patients and 37% of placebo patients. Discontinuations due to adverse events were reported for 6% of both study groups. In the bicalutamide-controlled study of chemotherapy-naïve patients, Grade 3-4 adverse reactions were reported in 38.8% of XTANDI patients and 37.6% of bicalutamide patients. Discontinuations due to adverse events were reported for 7.6% of XTANDI patients and 6.3% of bicalutamide patients.

Lab Abnormalities: In the two placebo-controlled trials, Grade 1-4 neutropenia occurred in 15% of XTANDI patients (1% Grade 3-4) and 6% of placebo patients (0.5% Grade 3-4). Grade 1-4 thrombocytopenia occurred in 6% of XTANDI patients (0.3% Grade 3-4) and 5% of placebo patients (0.5% Grade 3-4).

Grade 1-4 elevations in ALT occurred in 10% of XTANDI patients

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If co-administration is necessary, reduce the dose of XTANDI.

(0.2% Grade 3-4) and 16% of placebo patients (0.2% Grade 3-4).

Grade 1-4 elevations in bilirubin occurred in 3% of XTANDI patients (0.1% Grade 3-4) and 2% of placebo patients (no Grade 3-4).

Avoid strong CYP3A4 inducers as they can decrease the plasma exposure to XTANDI. If co-administration is necessary, increase the dose of XTANDI.

Infections: In the study of patients taking XTANDI who previously received docetaxel, 1% of XTANDI patients compared to 0.3% of placebo patients died from infections or sepsis. In the study of chemotherapy-naïve patients, 1 patient in each treatment group (0.1%) had an infection resulting in death.

Effect of XTANDI on Other Drugs Avoid CYP3A4, CYP2C9, and CYP2C19 substrates with a narrow therapeutic index, as XTANDI may decrease the plasma exposures of these drugs. If XTANDI is co-administered with warfarin (CYP2C9 substrate), conduct additional INR monitoring.

Falls (including fall-related injuries) occurred in 9% of XTANDI patients and 4% of placebo patients in the two placebocontrolled trials. Falls were not associated with loss of consciousness or seizure. Fall-related injuries were more severe in XTANDI patients, and included non-pathologic fractures, joint injuries, and hematomas.

Please see adjacent pages for Brief Summary of Full Prescribing Information.

The National Comprehensive Cancer Network makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.

References: 1. XTANDI [package insert]. Northbrook, IL: Astellas, Inc. 2. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Prostate Cancer V.2.2017. © National Comprehensive Cancer Network, Inc. 2017. All rights reserved. Accessed [November 14, 2017]. To view the most recent and complete version of the guideline, go online to NCCN.org. 3. Beer TM, Armstrong AJ, Rathkopf DE, et al., for the PREVAIL Investigators. Enzalutamide in metastatic prostate cancer before chemotherapy.

N Engl J Med 2014;371(5):424-33.

Hypertension occurred in 11% of XTANDI patients and 4% of placebo patients in the two placebo-controlled trials. No patients experienced hypertensive crisis. Medical history of hypertension was balanced between arms. Hypertension led to study discontinuation in < 1% of patients in each arm.

Drug Interactions Effect of Other Drugs on XTANDI Avoid strong CYP2C8 inhibitors, as they can increase the plasma exposure to XTANDI.

© 2018 Astellas Pharma US, Inc. All rights reserved. Printed in USA. 076-3069-PM 1/18 XTANDI, Astellas, and the flying star logo are registered trademarks of Astellas Pharma Inc.

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XTANDI (enzalutamide) capsules is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC).

the two placebo-controlled clinical trials were asthenia/fatigue, back pain, decreased appetite, constipation, arthralgia, diarrhea, hot flush, upper respiratory tract infection, peripheral edema, dyspnea, musculoskeletal pain, weight decreased, headache, hypertension, and dizziness/vertigo. In the bicalutamide-controlled study of chemotherapy-naïve patients, the most common adverse reactions (≥ 10%) reported in XTANDI patients were asthenia/ fatigue, back pain, musculoskeletal pain, hot flush, hypertension, nausea, constipation, upper respiratory tract infection, diarrhea, and weight loss.

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Indication

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Upon progression on GnRH therapy* in mCRPC1

To reduce the risk of radiographic progression in metastatic CRPC†1 National Comprehensive Cancer Network® (NCCN®)2 The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) recommend enzalutamide (XTANDI) as a Category 1 first-line treatment option for patients with metastatic CRPC||2

83% reduction in the risk of radiographic progression or death

‡

with XTANDI + GnRH therapy* vs placebo + GnRH therapy*1 • HR = 0.17 (95% CI, 0.14-0.21); P < 0.0001 Overall survival, co-primary endpoint§: 23% reduction in risk of death with XTANDI + GnRH therapy* vs placebo + GnRH therapy* (HR = 0.77 [95% CI, 0.67-0.88])1

CI, confidence interval; GnRH therapy, gonadotropin-releasing hormone therapy; HR, hazard ratio; mCRPC, metastatic castration-resistant prostate cancer. *Or after bilateral orchiectomy.1 † As seen in the PREVAIL trial (Study 2): a multinational, double-blind, randomized, phase 3 trial that enrolled 1717 patients with metastatic CRPC who progressed on GnRH therapy or after bilateral orchiectomy, and who had not received prior cytotoxic chemotherapy. All patients continued on GnRH therapy.1,3 ‡ Radiographic progression was assessed by blinded Independent Central Review (ICR) per Prostate Cancer Clinical Trials Working Group 2 (PCWG2) criteria for bone lesion progression and/or Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) for soft tissue/visceral disease progression.1,3 § An updated survival analysis was conducted when 784 deaths were observed. The median follow-up time was 31 months. Results from this analysis were consistent with those from the prespecified interim analysis.1 II Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.2

Learn more about XTANDI at XtandiHCP.com

Important Safety Information Contraindications XTANDI is not indicated for women. XTANDI can cause fetal harm and potential loss of pregnancy.

Warnings and Precautions Seizure occurred in 0.5% of patients receiving XTANDI in clinical studies. In a study of patients with predisposing factors, seizures were reported in 2.2% of patients. See section 5.1 of the Prescribing Information for the list of predisposing factors. It is unknown whether anti-epileptic medications will prevent seizures with XTANDI. Permanently discontinue XTANDI in patients who develop a seizure during treatment.

Posterior Reversible Encephalopathy Syndrome (PRES) In post approval use, there have been reports of PRES in patients receiving XTANDI. PRES is a neurological disorder which can present with rapidly evolving symptoms including seizure, headache, lethargy, confusion, blindness, and other visual and neurological disturbances, with or without associated hypertension. A diagnosis of PRES requires confirmation by brain imaging, preferably MRI. Discontinue XTANDI in patients who develop PRES.

Adverse Reactions The most common adverse reactions (≥ 10%) that occurred more commonly (≥ 2% over placebo) in the XTANDI patients from

In the placebo-controlled study of patients taking XTANDI who previously received docetaxel, Grade 3 and higher adverse reactions were reported among 47% of XTANDI patients and 53% of placebo patients. Discontinuations due to adverse events were reported for 16% of XTANDI patients and 18% of placebo patients.

In the placebo-controlled study of chemotherapy-naïve patients, Grade 3-4 adverse reactions were reported in 44% of XTANDI patients and 37% of placebo patients. Discontinuations due to adverse events were reported for 6% of both study groups. In the bicalutamide-controlled study of chemotherapy-naïve patients, Grade 3-4 adverse reactions were reported in 38.8% of XTANDI patients and 37.6% of bicalutamide patients. Discontinuations due to adverse events were reported for 7.6% of XTANDI patients and 6.3% of bicalutamide patients.

Lab Abnormalities: In the two placebo-controlled trials, Grade 1-4 neutropenia occurred in 15% of XTANDI patients (1% Grade 3-4) and 6% of placebo patients (0.5% Grade 3-4). Grade 1-4 thrombocytopenia occurred in 6% of XTANDI patients (0.3% Grade 3-4) and 5% of placebo patients (0.5% Grade 3-4).

Grade 1-4 elevations in ALT occurred in 10% of XTANDI patients

FS:9” F:10.5”

If co-administration is necessary, reduce the dose of XTANDI.

(0.2% Grade 3-4) and 16% of placebo patients (0.2% Grade 3-4).

Grade 1-4 elevations in bilirubin occurred in 3% of XTANDI patients (0.1% Grade 3-4) and 2% of placebo patients (no Grade 3-4).

Avoid strong CYP3A4 inducers as they can decrease the plasma exposure to XTANDI. If co-administration is necessary, increase the dose of XTANDI.

Infections: In the study of patients taking XTANDI who previously received docetaxel, 1% of XTANDI patients compared to 0.3% of placebo patients died from infections or sepsis. In the study of chemotherapy-naïve patients, 1 patient in each treatment group (0.1%) had an infection resulting in death.

Effect of XTANDI on Other Drugs Avoid CYP3A4, CYP2C9, and CYP2C19 substrates with a narrow therapeutic index, as XTANDI may decrease the plasma exposures of these drugs. If XTANDI is co-administered with warfarin (CYP2C9 substrate), conduct additional INR monitoring.

Falls (including fall-related injuries) occurred in 9% of XTANDI patients and 4% of placebo patients in the two placebocontrolled trials. Falls were not associated with loss of consciousness or seizure. Fall-related injuries were more severe in XTANDI patients, and included non-pathologic fractures, joint injuries, and hematomas.

Please see adjacent pages for Brief Summary of Full Prescribing Information.

The National Comprehensive Cancer Network makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.

References: 1. XTANDI [package insert]. Northbrook, IL: Astellas, Inc. 2. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Prostate Cancer V.2.2017. © National Comprehensive Cancer Network, Inc. 2017. All rights reserved. Accessed [November 14, 2017]. To view the most recent and complete version of the guideline, go online to NCCN.org. 3. Beer TM, Armstrong AJ, Rathkopf DE, et al., for the PREVAIL Investigators. Enzalutamide in metastatic prostate cancer before chemotherapy.

N Engl J Med 2014;371(5):424-33.

Hypertension occurred in 11% of XTANDI patients and 4% of placebo patients in the two placebo-controlled trials. No patients experienced hypertensive crisis. Medical history of hypertension was balanced between arms. Hypertension led to study discontinuation in < 1% of patients in each arm.

Drug Interactions Effect of Other Drugs on XTANDI Avoid strong CYP2C8 inhibitors, as they can increase the plasma exposure to XTANDI.

© 2018 Astellas Pharma US, Inc. All rights reserved. Printed in USA. 076-3069-PM 1/18 XTANDI, Astellas, and the flying star logo are registered trademarks of Astellas Pharma Inc.

FS:9” F:10.5”

B:15”

XTANDI (enzalutamide) capsules is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC).

the two placebo-controlled clinical trials were asthenia/fatigue, back pain, decreased appetite, constipation, arthralgia, diarrhea, hot flush, upper respiratory tract infection, peripheral edema, dyspnea, musculoskeletal pain, weight decreased, headache, hypertension, and dizziness/vertigo. In the bicalutamide-controlled study of chemotherapy-naïve patients, the most common adverse reactions (≥ 10%) reported in XTANDI patients were asthenia/ fatigue, back pain, musculoskeletal pain, hot flush, hypertension, nausea, constipation, upper respiratory tract infection, diarrhea, and weight loss.

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2 Renal & Urology News

JANUARY/ FEBRUARY 2018 www.renalandurologynews.com

Robotic Kidney Transplantation Safe, Feasible ROBOT-ASSISTED KIDNEY transplantation (RAKT) is associated with low complication rates, rapid recovery, and excellent graft function when performed by surgeons with robotic and kidney transplantation experience, according to a European study.

In what they believe is the largest reported multicenter prospective study of RAKT, Alberto Breda, MD, of Autonoma University of Barcelona in Spain, and colleagues evaluated perioperative and early postoperative surgical outcomes among 120 patients (75 men

XTANDI® (enzalutamide) capsules for oral use Initial U.S. Approval: 2012 BRIEF SUMMARY OF PRESCRIBING INFORMATION The following is a brief summary. Please see the package insert for full prescribing information.

INDICATIONS AND USAGE XTANDI is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC).

CONTRAINDICATIONS Pregnancy XTANDI can cause fetal harm and potential loss of pregnancy.

WARNINGS AND PRECAUTIONS Seizure Seizure occurred in 0.5% of patients receiving XTANDI in clinical studies. In these trials patients with predisposing factors for seizure were generally excluded. Seizure occurred from 31 to 603 days after initiation of XTANDI. Patients experiencing seizures were permanently discontinued from therapy and all seizure events resolved.

In a single-arm trial designed to assess the risk of seizure in patients with pre-disposing factors for seizure, 8 of 366 (2.2%) XTANDI-treated patients experienced a seizure. Three of the 8 patients experienced a second seizure during continued treatment with XTANDI after their first seizure resolved. It is unknown whether anti-epileptic medications will prevent seizures with XTANDI. Patients in the study had one or more of the following pre-disposing factors: the use of medications that may lower the seizure threshold (~ 54%), history of traumatic brain or head injury (~ 28%), history of cerebrovascular accident or transient ischemic attack (~ 24%), and Alzheimer’s disease, meningioma, or leptomeningeal disease from prostate cancer, unexplained loss of consciousness within the last 12 months, past history of seizure, presence of a space occupying lesion of the brain, history of arteriovenous malformation, or history of brain infection (all < 5%). Approximately 17% of patients had more than one risk factor.

Advise patients of the risk of developing a seizure while receiving XTANDI and of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others.

Permanently discontinue XTANDI in patients who develop a seizure during treatment.

Posterior Reversible Encephalopathy Syndrome (PRES) There have been reports of posterior reversible encephalopathy syndrome (PRES) in patients receiving XTANDI. PRES is a neurological disorder which can present with rapidly evolving symptoms including seizure, headache, lethargy, confusion, blindness, and other visual and neurological disturbances, with or without associated hypertension. A diagnosis of PRES requires confirmation by brain imaging, preferably magnetic resonance imaging (MRI). Discontinue XTANDI in patients who develop PRES. ADVERSE REACTIONS 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 practice.

Three randomized clinical trials enrolled patients with metastatic prostate cancer that has progressed on androgen deprivation therapy (GnRH therapy or bilateral orchiectomy), a disease setting that is also defined as metastatic CRPC. Two trials were placebo-controlled (Studies 1 and 2), and one trial was bicalutamidecontrolled (Study 3). In Studies 1 and 2, patients received XTANDI 160 mg or placebo orally once daily. In Study 3, patients received XTANDI 160 mg or bicalutamide 50 mg orally once daily. All patients continued androgen deprivation therapy. Patients were allowed, but not required, to take glucocorticoids.

The most common adverse reactions (≥ 10%) that occurred more commonly (≥ 2% over placebo) in the XTANDI-treated patients from the two randomized placebo-controlled clinical trials were asthenia/fatigue, back pain, decreased appetite, constipation, arthralgia, diarrhea, hot flush, upper respiratory tract infection, peripheral edema, dyspnea, musculoskeletal pain, weight decreased, headache, hypertension, and dizziness/vertigo.

and 45 women) from 8 European centers who underwent the procedure, of whom 118 received a kidney from a living donor. Patients had a median age at surgery of 43 years, median dialysis duration of 365 days, and a minimum follow-up period of 1 year.

Study 1: XTANDI versus Placebo in Metastatic CRPC Following Chemotherapy Study 1 enrolled 1199 patients with metastatic CRPC who had previously received docetaxel. The median duration of treatment was 8.3 months with XTANDI and 3.0 months with placebo. During the trial, 48% of patients on the XTANDI arm and 46% of patients on the placebo arm received glucocorticoids.

Grade 3 and higher adverse reactions were reported among 47% of XTANDI-treated patients and 53% of placebo-treated patients. Discontinuations due to adverse events were reported for 16% of XTANDI-treated patients and 18% of placebo-treated patients. The most common adverse reaction leading to treatment discontinuation was seizure, which occurred in 0.9% of the XTANDI-treated patients compared to none (0%) of the placebo-treated patients. Table 1 shows adverse reactions reported in Study 1 that occurred at a ≥ 2% higher frequency in the XTANDI arm compared to the placebo arm.

Table 1. Adverse Reactions in Study 1 XTANDI Placebo N = 800 N = 399 Grade Grade Grade Grade a 3-4 1-4 3-4 1-4 (%) (%) (%) (%) General Disorders Asthenic 50.6 9.0 44.4 9.3 Conditionsb Peripheral 15.4 1.0 13.3 0.8 Edema Musculoskeletal And Connective Tissue Disorders Back Pain 26.4 5.3 24.3 4.0 Arthralgia 20.5 2.5 17.3 1.8 Musculoskeletal 15.0 1.3 11.5 0.3 Pain Muscular 9.8 1.5 6.8 1.8 Weakness Musculoskeletal 2.6 0.3 0.3 0.0 Stiffness Gastrointestinal Disorders Diarrhea 21.8 1.1 17.5 0.3 Vascular Disorders Hot Flush 20.3 0.0 10.3 0.0 Hypertension 6.4 2.1 2.8 1.3 Nervous System Disorders Headache 12.1 0.9 5.5 0.0 Dizzinessc 9.5 0.5 7.5 0.5 Spinal Cord Compression and Cauda 7.4 6.6 4.5 3.8 Equina Syndrome Paresthesia 6.6 0.0 4.5 0.0 Mental 4.3 0.3 1.8 0.0 Impairment Disordersd Hypoesthesia 4.0 0.3 1.8 0.0 Infections And Infestations Upper 10.9 0.0 6.5 0.3 Respiratory Tract Infectione Lower Respiratory 8.5 2.4 4.8 1.3 Tract And Lung Infectionf Psychiatric Disorders Insomnia 8.8 0.0 6.0 0.5 Anxiety 6.5 0.3 4.0 0.0 Renal And Urinary Disorders Hematuria 6.9 1.8 4.5 1.0 Pollakiuria 4.8 0.0 2.5 0.0 Injury, Poisoning And Procedural Complications Fall 4.6 0.3 1.3 0.0 Non-pathologic 4.0 1.4 0.8 0.3 Fractures Skin And Subcutaneous Tissue Disorders Pruritus 3.8 0.0 1.3 0.0 Dry Skin 3.5 0.0 1.3 0.0 Respiratory Disorders Epistaxis 3.3 0.1 1.3 0.3 a b c d

CTCAE v4.

Includes asthenia and fatigue.

Includes dizziness and vertigo.

Includes amnesia, memory impairment, cognitive disorder, and disturbance in attention. e Includes nasopharyngitis, upper respiratory tract infection, sinusitis, rhinitis, pharyngitis, and laryngitis. f Includes pneumonia, lower respiratory tract infection, bronchitis, and lung infection.

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The median operative, console, and vascular suture times were 250, 160, and 38 minutes, respectively, Dr Breda’s group reported in European Urology (2018;73:273-281). The median estimated blood loss was 150 mL. The median warm ischemia and cold Study 2: XTANDI versus Placebo in Chemotherapynaïve Metastatic CRPC Study 2 enrolled 1717 patients with metastatic CRPC who had not received prior cytotoxic chemotherapy, of whom 1715 received at least one dose of study drug. The median duration of treatment was 17.5 months with XTANDI and 4.6 months with placebo. Grade 3-4 adverse reactions were reported in 44% of XTANDI-treated patients and 37% of placebo-treated patients. Discontinuations due to adverse events were reported for 6% of XTANDI-treated patients and 6% of placebo-treated patients. The most common adverse reaction leading to treatment discontinuation was fatigue/asthenia, which occurred in 1% of patients on each treatment arm. Table 2 includes adverse reactions reported in Study 2 that occurred at a ≥ 2% higher frequency in the XTANDI arm compared to the placebo arm.

Table 2. Adverse Reactions in Study 2 XTANDI Placebo N = 871 N = 844 Grade Grade Grade Grade 3-4 1-4 3-4 1-4a (%) (%) (%) (%) General Disorders Asthenic 46.9 3.4 33.0 2.8 Conditionsb Peripheral 11.5 0.2 8.2 0.4 Edema Musculoskeletal And Connective Tissue Disorders Back Pain 28.6 2.5 22.4 3.0 Arthralgia 21.4 1.6 16.1 1.1 Gastrointestinal Disorders Constipation 23.2 0.7 17.3 0.4 Diarrhea 16.8 0.3 14.3 0.4 Vascular Disorders Hot Flush 18.0 0.1 7.8 0.0 Hypertension 14.2 7.2 4.1 2.3 Nervous System Disorders 11.3 0.3 7.1 0.0 Dizzinessc Headache 11.0 0.2 7.0 0.4 Dysgeusia 7.6 0.1 3.7 0.0 Mental 5.7 0.0 1.3 0.1 Impairment Disordersd Restless Legs 2.1 0.1 0.4 0.0 Syndrome Respiratory Disorders 11.0 0.6 8.5 0.6 Dyspneae Infections And Infestations Upper 16.4 0.0 10.5 0.0 Respiratory Tract Infectionf Lower Respiratory 7.9 1.5 4.7 1.1 Tract And Lung Infectiong Psychiatric Disorders Insomnia 8.2 0.1 5.7 0.0 Renal And Urinary Disorders Hematuria 8.8 1.3 5.8 1.3 Injury, Poisoning And Procedural Complications Fall 12.7 1.6 5.3 0.7 Non-Pathological 8.8 2.1 3.0 1.1 Fracture Metabolism and Nutrition Disorders Decreased 18.9 0.3 16.4 0.7 Appetite Investigations Weight 12.4 0.8 8.5 0.2 Decreased Reproductive System and Breast Disorders 1.4 3.4 0.0 0.0 Gynecomastia a b c d

CTCAE v4.

Includes asthenia and fatigue.

Includes dizziness and vertigo.

Includes amnesia, memory impairment, cognitive disorder, and disturbance in attention. e Includes dyspnea, exertional dyspnea, and dyspnea at rest. f Includes nasopharyngitis, upper respiratory tract infection, sinusitis, rhinitis, pharyngitis, and laryngitis. g Includes pneumonia, lower respiratory tract infection, bronchitis, and lung infection.

Study 3: XTANDI versus Bicalutamide in Chemotherapynaïve Metastatic CRPC Study 3 enrolled 375 patients with metastatic CRPC who had not received prior cytotoxic chemotherapy, of whom 372 received at least one dose of study drug. The median duration of treatment was 11.6 months with XTANDI

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ischemia times were 2 minutes and 34 minutes, respectively. No major ­intraoperative complications occurred, but 2 patients required conversion to an open procedure. The median postoperative estimated glomerular filtration rate on postoperative day 1, 3, 7, and 30 was 21.2, 45.0, 52.6, and 58.0 mL/min/1.73 m2, respectively, according to the investigators. Five patients (4.2%) experienced delayed graft and 5.8 months with bicalutamide. Discontinuations with an adverse event as the primary reason were reported for 7.6% of XTANDI-treated patients and 6.3% of bicalutamidetreated patients. The most common adverse reactions leading to treatment discontinuation were back pain and pathological fracture, which occurred in 3.8% of XTANDItreated patients for each event and in 2.1% and 1.6% of bicalutamide-treated patients, respectively. Table 3 shows overall and common adverse reactions (≥ 10%) in XTANDItreated patients.

Table 3. Adverse Reactions in Study 3 XTANDI Bicalutamide N = 183 N = 189 Grade Grade Grade Grade a 1-4 3-4 1-4a 3-4 (%) (%) (%) (%) Overall 94.0 38.8 94.2 37.6 General Disorders Asthenic 31.7 1.6 22.8 1.1 Conditionsb Musculoskeletal And Connective Tissue Disorders Back Pain 19.1 2.7 18.0 1.6 Musculoskeletal 16.4 1.1 14.3 0.5 c Pain Vascular Disorders Hot Flush 14.8 0.0 11.1 0.0 Hypertension 14.2 7.1 7.4 4.2 Gastrointestinal Disorders Nausea 14.2 0.0 17.5 0.0 Constipation 12.6 1.1 13.2 0.5 Diarrhea 11.5 0.0 9.0 1.1 Infections And Infestations Upper 12.0 0.0 6.3 0.5 Respiratory Tract Infectiond Investigational Weight Loss 10.9 0.5 7.9 0.5 a b c d

CTCAE v 4.

Including asthenia and fatigue.

Including musculoskeletal pain and pain in extremity.

Including nasopharyngitis, upper respiratory tract infection, sinusitis, rhinitis, pharyngitis, and laryngitis.

Laboratory Abnormalities In the two randomized placebo-controlled clinical trials, Grade 1-4 neutropenia occurred in 15% of patients treated with XTANDI (1% Grade 3-4) and in 6% of patients treated with placebo (0.5% Grade 3-4). The incidence of Grade 1-4 thrombocytopenia was 6% of patients treated with XTANDI (0.3% Grade 3-4) and 5% of patients treated with placebo (0.5% Grade 3-4). Grade 1-4 elevations in ALT occurred in 10% of patients treated with XTANDI (0.2% Grade 3-4) and 16% of patients treated with placebo (0.2% Grade 3-4). Grade 1-4 elevations in bilirubin occurred in 3% of patients treated with XTANDI (0.1% Grade 3-4) and 2% of patients treated with placebo (no Grade 3-4).

Infections In Study 1, 1% of patients treated with XTANDI compared to 0.3% of patients treated with placebo died from infections or sepsis. In Study 2, 1 patient in each treatment group (0.1%) had an infection resulting in death.

Falls and Fall-related Injuries In the two randomized placebo-controlled clinical trials, falls including fall-related injuries, occurred in 9% of patients treated with XTANDI compared to 4% of patients treated with placebo. Falls were not associated with loss of consciousness or seizure. Fall-related injuries were more severe in patients treated with XTANDI and included non-pathologic fractures, joint injuries, and hematomas.

Hypertension In the two randomized placebo-controlled trials, hypertension was reported in 11% of patients receiving XTANDI and 4% of patients receiving placebo.

No patients experienced hypertensive crisis. Medical history of hypertension was balanced between arms.

Hypertension led to study discontinuation in < 1% of patients in each arm.

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

Body as a Whole: hypersensitivity (tongue edema, lip edema, and pharyngeal edema)

function. Dr Breda and his colleagues reported 1 case of wound infection, 3 cases of ileus, and 4 cases of bleeding.

“Surgical data show that RAKT is safe, feasible, and reproducible when performed by surgeons with experience in both robotic and KT surgery,” the authors concluded. “Use of a robotic technique also has low complication rates in selected cases and yields excellent graft function.”

Gastrointestinal Disorders: vomiting Neurological Disorders: posterior reversible encephalopathy syndrome (PRES) Skin and Subcutaneous Tissue Disorders: rash DRUG INTERACTIONS Drugs that Inhibit CYP2C8 Co-administration of a strong CYP2C8 inhibitor (gemfibrozil) increased the composite area under the plasma concentration-time curve (AUC) of enzalutamide plus N-desmethyl enzalutamide by 2.2-fold. Co-administration of XTANDI with strong CYP2C8 inhibitors should be avoided if possible. If co-administration of XTANDI with a strong CYP2C8 inhibitor cannot be avoided, reduce the dose of XTANDI. Drugs that Induce CYP3A4 Co-administration of rifampin (strong CYP3A4 inducer and moderate CYP2C8 inducer) decreased the composite AUC of enzalutamide plus N-desmethyl enzalutamide by 37%. Co-administration of strong CYP3A4 inducers (e.g., carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine) with XTANDI should be avoided if possible. St John’s wort may decrease enzalutamide exposure and should be avoided. If co-administration of a strong CYP3A4 inducer with XTANDI cannot be avoided, increase the dose of XTANDI. Effect of XTANDI on Drug Metabolizing Enzymes Enzalutamide is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer in humans. At steady state, XTANDI reduced the plasma exposure to midazolam (CYP3A4 substrate), warfarin (CYP2C9 substrate), and omeprazole (CYP2C19 substrate). Concomitant use of XTANDI with narrow therapeutic index drugs that are metabolized by CYP3A4 (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus and tacrolimus), CYP2C9 (e.g., phenytoin, warfarin) and CYP2C19 (e.g., S-mephenytoin) should be avoided, as enzalutamide may decrease their exposure. If co-administration with warfarin cannot be avoided, conduct additional INR monitoring.

USE IN SPECIFIC POPULATIONS Pregnancy Risk Summary XTANDI is contraindicated for use in pregnant women because the drug can cause fetal harm and potential loss of pregnancy. XTANDI is not indicated for use in females.

There are no human data on the use of XTANDI in pregnant women. In animal reproduction studies, oral administration of enzalutamide in pregnant mice during organogenesis caused adverse developmental effects at doses lower than the maximum recommended human dose.

Animal Data In an embryo-fetal developmental toxicity study in mice, enzalutamide caused developmental toxicity when administered at oral doses of 10 or 30 mg/kg/day throughout the period of organogenesis (gestational days 6-15). Findings included embryo-fetal lethality (increased post-implantation loss and resorptions) and decreased anogenital distance at ≥ 10 mg/kg/day, and cleft palate and absent palatine bone at 30 mg/kg/day. Doses of 30 mg/kg/day caused maternal toxicity. The doses tested in mice (1, 10 and 30 mg/kg/day) resulted in systemic exposures (AUC) approximately 0.04, 0.4 and 1.1 times, respectively, the exposures in patients. Enzalutamide did not cause developmental toxicity in rabbits when administered throughout the period of organogenesis (gestational days 6-18) at dose levels up to 10 mg/kg/day (approximately 0.4 times the exposures in patients based on AUC).

Lactation Risk Summary XTANDI is not indicated for use in females. There is no information available on the presence of XTANDI in human milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production.

Enzalutamide and/or its metabolites were present in milk of lactating rats.

Females and Males of Reproductive Potential Contraception Males Based on findings in animal reproduction studies, advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 3 months after the final dose of XTANDI. Infertility Based on animal studies, XTANDI may impair fertility in males of reproductive potential.

Pediatric Use Safety and effectiveness of XTANDI in pediatric patients have not been established.

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Dr Breda and his colleagues noted that all of the surgical teams involved in the study have thorough expertise in robotic-assisted surgery and open KT. All surgeons had rehearsed the robotic technique on animal models before using it on patients, with proctoring by a more experienced RAKT surgeon during training and when performing the first case(s) in their own center, they explained.

Geriatric Use Of 1671 patients who received XTANDI in the two randomized placebo-controlled clinical trials, 75% were 65 and over, while 31% were 75 and over. No overall differences in safety or effectiveness were observed between these 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 Renal Impairment A dedicated renal impairment trial for XTANDI has not been conducted. Based on the population pharmacokinetic analysis using data from clinical trials in patients with metastatic CRPC and healthy volunteers, no significant difference in enzalutamide clearance was observed in patients with pre-existing mild to moderate renal impairment (30 mL/min ≤ creatinine clearance [CrCL] ≤ 89 mL/min) compared to patients and volunteers with baseline normal renal function (CrCL ≥ 90 mL/min).

No initial dosage adjustment is necessary for patients with mild to moderate renal impairment. Severe renal impairment (CrCL < 30 mL/min) and end-stage renal disease have not been assessed.

Patients with Hepatic Impairment Dedicated hepatic impairment trials compared the composite systemic exposure of enzalutamide plus N-desmethyl enzalutamide in volunteers with baseline mild, moderate, or severe hepatic impairment (ChildPugh Class A, B, or C, respectively) versus healthy controls with normal hepatic function. The composite AUC of enzalutamide plus N-desmethyl enzalutamide was similar in volunteers with mild, moderate, or severe baseline hepatic impairment compared to volunteers with normal hepatic function. No initial dosage adjustment is necessary for patients with baseline mild, moderate, or severe hepatic impairment.

OVERDOSAGE In the event of an overdose, stop treatment with XTANDI and initiate general supportive measures taking into consideration the half-life of 5.8 days. In a dose escalation study, no seizures were reported at ≤ 240 mg daily, whereas 3 seizures were reported, 1 each at 360 mg, 480 mg, and 600 mg daily. Patients may be at increased risk of seizure following an overdose.

NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies have not been conducted to evaluate the carcinogenic potential of enzalutamide.

Enzalutamide did not induce mutations in the bacterial reverse mutation (Ames) assay and was not genotoxic in either the in vitro mouse lymphoma thymidine kinase (Tk) gene mutation assay or the in vivo mouse micronucleus assay.

Based on nonclinical findings in repeat-dose toxicology studies, which were consistent with the pharmacological activity of enzalutamide, male fertility may be impaired by treatment with XTANDI. In a 26-week study in rats, atrophy of the prostate and seminal vesicles was observed at ≥ 30 mg/kg/day (equal to the human exposure based on AUC). In 4-, 13-, and 39-week studies in dogs, hypospermatogenesis and atrophy of the prostate and epididymides were observed at ≥ 4 mg/kg/day (0.3 times the human exposure based on AUC).

Manufactured for and Distributed by: Astellas Pharma US, Inc., Northbrook, IL 60062 Marketed by: Astellas Pharma US, Inc., Northbrook, IL 60062 Pfizer Inc., New York, NY 10017 Revised: July 2017 16K089-XTA-WPI Rx Only © 2017 Astellas Pharma US, Inc. XTANDI® is a registered trademark of Astellas Pharma Inc.

076-2626-PM

Renal & Urology News 3

In general, the authors observed, the typical advantages of robotic surgery relate to the use of articulated instruments, a 3D view, superb magnification, and good surgeon ergonomics.

Patients with end-stage renal disease generally are immunocompromised and fragile, the authors explained.

Consequently, they may benefit significantly from KT performed using a minimally invasive approach.

The investigators said one of the limitations of their study is possible bias in the selection process. The 8 centers that participated in the study are high-volume centers, they noted. “Despite this, a limited number of recipients were included in the study,” Dr Breda’s team wrote. “This can be explained not only by the inclusion and exclusion criteria but also by the cost limitations of the procedure … and patient preference.”

Low complication rates, rapid recovery, and excellent graft function possible.

Other limitations included the lack of a control group of patients who underwent open KT from a living donor and the fact that not all centers enrolled patients at the same time, the authors stated.

In an editorial accompanying the study, Akshay Sood, MD, and Mani Menon, MD, of the Vattikuti Urology Institute at Henry Ford Hospital in Detroit, commented: “The authors are congratulated for successfully undertaking this study and demonstrating that robotic kidney transplantation can be safely adopted by surgeons of varying robotic experience via a structured preclinical and clinical mentorship program.”

They pointed out, however, that it is important to study in detail the patients who had complications. “We understand that it may not be feasible to report institute-specific analysis for the purposes of publication, but an internal root-cause analysis must be performed.”

The importance of such an analysis was highlighted by Pranjal Modi, MD, and colleagues in their study of laparoscopic KT in 72 patients, the editorialists noted. The analysis, published in Transplantation (2013;95:100-105), revealed that grafts left intraperitoneally were associated with a high risk of delayed graft torsion (5.9%), leading to routine extraperitoneal grafts, with a subsequent graft torsion rate of 0%. n

4 Renal & Urology News

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FROM THE MEDICAL DIRECTOR EDITORIAL ADVISORY BOARD

Guidelines Disconnect: Patients’ Voice Absent

A

decade ago, in one of my first editorials for Renal & Urology News, I argued that clinical practice guidelines needed to be developed by hands-on clinicians and community practitioners as opposed to the academicians who have minimal to no patient care responsibilities. In nephrology there are many renowned academicians who hardly see any patients but are invited to be core contributors to important practice guideline meetings and consensus conferences. I argued that there are serious implications for this discrepancy, including a guideline disconnect from the real-world problems of patient care. Another issue in academia is biased opinions, which may be due to industry relationships as well as egos that may severely cloud academicians’ judgment, given that many academicians—even those with minimal ties with pharmaceutical companies—feel comfortable and indeed prefer strongly to refer to their own opinions and own publications as the source of “good” guidelines.

In the past decade, patient-centered considerations have gained greater prominence, but practice guidelines generally do not reflect this. Lack of patient centeredness in many practice guidelines, particularly in nephrology, results from the absence of representatives from patient advocacy groups in most guideline meetings or consensus panels. A good example is dialysis practice guidelines, which recommend earlier dialysis initiation, more frequent dialysis, longer dialysis treatment sessions, and higher dialysis dose. These guidelines were developed by physicians who rarely ask dialysis patients how they feel about these recommendations. Practicing physicians may feel compelled to follow such guidelines to protect themselves against malpractice lawsuits, and dialysis companies have no choice but to optimize these expectations. Hence, in recent years, more patients are forced to undergo hemodialysis sessions of 4 hours or more, with its accompanying adverse effects, such as worsening cramps, low blood pressure episodes, post-dialysis fatigue, faster loss of residual kidney function, and other harms.

Another example pertains to patient-disconnected guidelines on dietary restrictions, such as low potassium and low phosphorus, diets. Overzealous potassium-restrictive guidelines, for instance, deprive patients of the fundamental bliss for fresh fruits and vegetables with high fibers, sadly leading to a higher likelihood of constipation that may paradoxically worsen hyperkalemia. Blaming patients’ dietary habits – and calling them “non-compliant” patients – for their poorly controlled hyperphosphatemia instead of better management of hyperparathyroidism (as opposed to tolerating parathyroid hormone levels as high as 600 pg/mL as a result of the newer guidelines) has led to more patient frustration. In the past, nephrology guidelines were spearheaded by grass-root organizations, such as kidney foundations. It is time for patient-centeredness to become the core component of clinical practice guidelines.

Kam Kalantar-Zadeh, MD, MPH, PhD Professor & Chief, Division of Nephrology & Hypertension University of California Irvine School of Medicine Orange, California

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 Professor & Chief Division of Nephrology & Hypertension University of California, Irvine School of Medicine Orange, Calif.

Urologists

Nephrologists

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

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

R. John Honey, MD Head, Division of Urology, Endourology/Kidney Stone Diseases St. Michael’s Hospital University of Toronto

David S. Goldfarb, MD Professor, Department of Medicine Clinical Chief New York University Langone Medical Center Chief of Nephrology, NY Harbor VA Medical Center

Stanton Honig, MD Department of Urology Yale University School of Medicine New Haven, CT J. Stephen Jones, MD, FACS President, Cleveland Clinic Regional Hospitals & Family Health Centers Professor & Horvitz/Miller Distinguished Chair in Urological Oncology 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 John K. Lattimer Professor of Urology Chair, Department of Urology Director, Urologic Oncology Columbia University College of Physicians and Surgeons, New York City

Rulan Parekh, MD, MS Associate Professor of Pediatrics and Medicine University of Toronto

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

Robert Provenzano, MD Chief, Section of Nephrology St. John Hospital and Medical Center Detroit

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

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

Renal & Urology News Staff Editor Web editor Production editor

Jody A. Charnow Natasha Persaud Kim Daigneau

Group art director, Haymarket Medical

Jennifer Dvoretz

Production manager

Krassi Varbanov

Production director Circulation manager National accounts manager Group Publisher Editorial director

Kathleen Millea Grinder Paul Silver William Canning Chad Holloway Kathleen Walsh Tulley

General manager, medical communications

Jim Burke, RPh

CEO, Haymarket Media Inc.

Lee Maniscalco

Renal & Urology News (ISSN 1550-9478) Volume 17, Number 1. Published bimonthly by Haymarket Media, Inc., 275 7th Avenue, 10th Floor, New York, NY 10001. For Advertising Sales & Editorial, call (646) 638-6000 (M–F, 9am–5pm, ET). Postmaster: Send address changes to Renal & Urology News, c/o Direct Medical Data, 10255 W. Higgins Rd., Suite 280, Rosemont, IL 60018.

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 © 2018.

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Contents

JANUARY/ FEBRUARY 2018

JANUARY/ FEBRUARY 2018 ■ VOLUME 17, ISSUE NUMBER 1

Urology 19

ONLINE

24

this month at renalandurologynews.com 25

Clinical Quiz Test your knowledge by taking our latest quiz at renalandurologynews.com/ ClinicalQuiz

26

Optimal PCa Salvage Therapy Unclear Definitive comparative effectiveness data are lacking for how best to treat radiorecurrent disease.

7-Month PSA in Treated mHSPC Is Prognostic Achieving a PSA level of 0.2 ng/mL or less at 7 months after initiation of androgen deprivation therapy is associated with longer overall survival.

PCa Gene Testing Guidelines Issued Recommendations from an international expert panel call for clinicians to ask about cancers among members of the maternal and paternal sides of a family.

New PCa Grading System Gains Wide Acceptance A 5-tier Gleason grade group system is now used routinely in pathology reports and patient counseling.

HIPAA Compliance Patient access to records and other important issues in 2018.

Drug Information

6

MRAs May Benefit Selected High-Risk HF Patients Mineralocorticoid receptor antagonist therapy is associated with a lower risk of all-cause hospitalization in heart failure patients with diabetes or chronic kidney disease.

8

Residual Renal Function Not Linked to ESA Need RRF in patients on chronic dialysis is not associated with reduced requirements for erythropoietin-stimulating agents.

20

Lupus Anticoagulant Increases Calciphylaxis Risk Lupus anticoagulant and combined thrombophilia are risk factors for the development of calciphylaxis among patients with late-stage chronic kidney disease.

22

Kidney Failure Associated With Low Albumin Levels End-stage renal disease is more likely to develop in individuals with serum albumin levels of 4.1 g/dL or below than in those with levels of 4.4 g/dL or higher.

Job Board Be sure to check our latest listings for professional openings across the United States.

News Coverage Visit our website for daily reports from the 2018 National Kidney Foundation Spring Clinical Meetings in Austin, Texas, April 10–14.

CALENDAR Annual Dialysis Conference Orlando, Florida March 3–6 European Association of Urology 2018 Congress Copenhagen, Denmark March 16–20.

National Kidney Foundation Spring Clinical Meeting Austin, Texas April 10–14 American Urological Association Annual Meeting San Francisco, CA May 18–21 ERA-EDTA 55th Congress Copenhagen, Denmark May 24–27 Canadian Urological Association Annual Meeting Halifax, Nova Scotia June 23–26.

International Continence Society Annual Meeting Philadelphia August 28–31

Nephrology

Search a comprehensive drug database for prescribing and other information on more than 4000 drugs.

Renal & Urology News 5

The combination of 3D printing process along with customizable tissue-mimicking materials provide a platform for creating real life, patient-specific organ models.

See our story on page 15

American Society of Nephrology Kidney Week New Orleans October 23–28

28

Departments 4

From the Medical Director Guidelines still lack patient input

10

News in Brief Sleep apnea is linked to interdialytic weight gain

32

Practice Management Nurse managers have a critical role in health care

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MRAs May Benefit Selected High-Risk HF Patients MINERALOCORTICOID receptor antagonist (MRA) therapy is associated with a lower risk of all-cause hospitalization in high-risk patients with heart failure and concomitant diabetes or chronic kidney disease (CKD), but the medications also increase patients’ risk of hospitalization with hyperkalemia or acute renal insufficiency, researchers reported.

MRAs are recommended for patients with symptomatic heart failure with an ejection fraction of 35% of less, but they frequently are underused in clinical practice, possibly because of concerns about the risks of hyperkalemia and worsening renal function, according to the investigators.

Using clinical registry data linked to Medicare claims, Lauren B. Cooper, MD, MHS, of Inova Heart & Vascular Institute, Inova Fairfax Hospital, Falls Church, Virginia, and colleagues studied 16,848 patients hospitalized with heart failure from 2005 and 2013 and who had a history of diabetes or CKD. Of these, 2067 (12.3%) received MRA therapy at discharge. A significantly

Hyperkalemia In weighted analyses, MRA use was associated with a significant 2-fold increased risk of readmission for hyperkalemia at 30 days and 42% and 28% increased risk at 1 and 3 years, respectively. In addition, MRA use was associated with a significant 31%,

17%, and 14% increased risk of 30-day, 1-year, and 3-year readmission with a diagnosis of acute renal insufficiency, respectively.

MRA use was associated with a significant 2.7-fold and 2.2-fold increased risk of readmission with a primary diagnosis of hyperkalemia at 1 and

3 years, respectively. Further, MRA use was associated with a significant 65%, 32%, and 18% increased risk of readmission with a primary diagnosis of acute renal insufficiency at 30 days and 1 and 3 years, respectively.

“Because of the overall decrease in the risk of hospitalization for patients

Lower readmission risk found in heart failure patients with diabetes or CKD. higher proportion of the MRA group than the no-MRA group had diabetes mellitus (86.6% vs 82.2%), whereas CKD was significantly less common in the MRA group (27.8% vs 36%).

Higher serum creatinine was associated with 34% lower odds of MRA use, but serum potassium level was not associated with MRA use.

Readmission rates The 1- and 3-year all-cause hospital readmission rates were significantly lower for the MRA than no-MRA group. The rates were 68.2% and 84.9%, respectively, for the MRA recipients compared with 72.2% and 88.2%, respectively, for the no-MRA group, Dr Cooper’s team reported online ahead of print in the Journal of the American Heart Association. After inverse probability weighting, MRA use was associated with an 8% and 7% lower risk of readmission at 1 and 3 years, respectively. MRA use was not associated with 30-day, 1-year, or 3-year mortality or 30-day all-cause readmission.

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treated with mineralocorticoid receptor antagonist therapy, the benefits of therapy may outweigh the risks in a high-risk population,” the investigators wrote.

Patients receiving MRA therapy and who had borderline or preserved ejection fraction had increased risks of readmission for hyperkalemia and acute renal insufficiency, Dr Cooper and her colleagues reported.

For the study, Dr Cooper’s team used data from the American Heart Association’s Get With the GuidelinesHeart Failure registry linked to Medicare claims.

Patients in the MRA group were significantly younger than those in the noMRA group (mean 76.3 vs 77.8 years).

Patients in both groups were predominantly white: 72.8% of the MRA group and 74.5% of the no-MRA group. The

MRA group had a significantly higher proportion of men than the no-MRA group (55.9% vs 49.9%).

Study limitations The investigators acknowledged study limitations. As with all observational studies, they stated, unmeasured confounders may have influenced results.

In addition, the study population was limited to Medicare fee-for-service

­ eneficiaries, so results may not be b generalizable to other populations.

Patients were discharged recently from a hospitalization for acute heart failure, so results may not apply to stable outpatients with heart failure, the researchers noted. Further, they pointed out that they only examined whether MRA therapy was prescribed at discharge, but they had no information about doses prescribed. n

8 Renal & Urology News

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Residual Renal Function Not Linked to ESA Need RESIDUAL RENAL function (RRF) in patients on chronic dialysis is not associated with reduced requirements for erythropoietin-stimulating agents (ESAs), according to a new study.

Elizabeth Helene Louw and Mogamat-Yazied Chothia, from the Faculty of Medicine and Health

Sciences at Stellenbosch University in Cape Town, South Africa, studied 100 patients on chronic dialysis (mean age 41 years). Of these, 36 patients had RRF, which the investigators defined as a 24-hour urine sample volume of 100 mL or greater. Results showed no significant difference in median

e­rythropoietin resistance index (ERI)—which the investigators used as a measure of ESA dose requirements— between those with and without RRF (9.5 vs 11, respectively), according to a paper published in BMC Nephrology (2017;18:336). ERI is defined as the weekly dose of ESA divided by patient

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weight and corrected for hemoglobin concentration.

The study also found no significant difference in median ERI between hemodialysis and peritoneal dialysis patients (10.8 vs 10.2) or in those using and not using renin-angiotensin-system blockers (11.6 vs 9.2, respectively). n

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Renal & Urology News 9

Predictors of RCC Bone Metastasis Identified ALKALINE phosphatase (ALP), calcium, and hemoglobin levels are independent risk factors for bone metastasis in patients with renal cell carcinoma (RCC), according to a recent report.

In a study of 372 patients with RCC, Zhi-Li Liu, MD, Zhi-Hong Zhang, MD, and colleagues at the First Affiliated

Hospital of Nanchang University in Nanchang, China, found significantly higher levels of these clinical factors in the patients with versus without bone metastasis. An ALP level above 105.5 U/L, a calcium level above 2.615 mmol/L, and a hemoglobin level below 11.15 g/dL had a sensitivity of 57.9%, 36.8%, and 71.1%,

respectively, and a specificity of 83.5%, 95.2%, and 65.3%, respectively, for predicting bone metastasis, the investigators reported in the Journal of Bone Oncology (2017;9:29-33). According to the investigators, intensive monitoring and bone scans are warranted for patients with newly diagnosed RCC who have these

levels of ALP, calcium, and hemoglobin.

The researchers stated that a combination of risk factors appeared to be more useful for predicting bone metastasis than each risk factor individually. ALP plus hemoglobin, hemoglobin plus calcium, ALP plus calcium, and a combination of all 3 had a specificity of 91%, 97.6%, 97.9%, and 98.2%, respectively.

Of the 372 patients (62.6% male, 37.4% female), 111 had metastatic disease; 38 of these patients had bone metastases. The overall cohort had a median age of 56 years. The most common histologic subtype was clear cell carcinoma (75.3% of cases). n

PN May Up Survival in cT1b RCC PARTIAL nephrectomy is associated with significantly better survival than radical nephrectomy for cT1b renal cell carcinoma (RCC), but survival outcomes associated with both surgical approaches are similar for patients with cT2 RCC, new data suggest.

Partial nephrectomy (PN) is the standard management for cT1a RCC, and there is a basis for expanding its indications to larger tumors (cT1b and cT2), investigators noted.

Vivek Venkatramani, MD, and colleagues at the University of Miami Miller School of Medicine used the National Cancer Data Base to identify patients with cT1b and cT2 RCC who underwent PN or radical nephrectomy (RN) from 1994 to 2013. Among patients with cT1b RCC, those who underwent PN had a significant 20% lower odds of death compared with those treated with RN, Dr Venkatramani’s team reported online ahead of print in Urologic Oncology. The investigators found no significant difference in overall survival rates between the surgical approaches among patients with cT2 RCC. In addition, unplanned readmission at 30 days was significantly more common in the PN than RN groups (4.2% vs 2.9%), but the groups had similar 30- and 90-day mortality rates. n

10 Renal & Urology News

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News in Brief

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

Short Takes ONS Users Miss Fewer Hemodialysis Sessions

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In addition, a high level of moderate

number of missed dialysis sessions,

to vigorous physical activity was associ-

researchers reported online in the

ated with 25% decreased odds of ED.

Journal of Renal Nutrition.

Increasing age and HbA1c level were

Debbie Benner, MA, RD, of DaVita Inc,

associated with an increasing risk of ED.

in Denver, and colleagues compared serum albumin levels of 3.5 g/dL or

BPH Risk May Be Lower Among Allopurinol Users

less: 3374 patients who participated

ALLOPURINOL USE is associated with

in an ONS pilot program in which

a decreased risk of being diagnosed

patients received intradialytic ONS

with benign prostatic hyperplasia (BPH),

and a like number of matched controls

researchers reported online in Prostate

in facilities not participating in the

Cancer and Prostatic Diseases.

2 groups of in-center HD patients with

pilot program. The ONS group had

In a study of 74,754 men, Ville

33% fewer missed dialysis treatments

Kukko, of the University of Tampere

compared with controls and a 69%

in Finland, and colleagues found that

decreased risk of death.

men using allopurinol had a 22% lower risk of a BPH diagnosis and a

ED Risk Is Associated With Handgrip Strength

19% and 33% decreased likelihood of

MEN WITH greater handgrip strength

surgery, respectively, after multivari-

have a lower risk of erectile dysfunc-

able adjustment. The investigators

tion (ED), new findings suggest.

observed that only body mass index

In a cross-sectional study of 1708

BPH medication use and BPH-related

(BMI) modified the risk association,

men, Ho Seok Chung, MD, and col-

with decreased risks found only

leagues at Chonnam National Universi-

among men with a BMI above the

ty Medical School in Gwangju, Korea,

median (27.3 kg/m2).

Neoadjuvant Chemo On the Rise Use of neoadjuvant chemotherapy for patients with muscle-invasive bladder cancer (MIBC) in the general population has been increasing, according to a study of 5582 patients who underwent cystectomy for MIBC in Ontario, Canada, from 1994 to 2013.

30

27%

25 20 15

12%

10 5 0

4% 1994 – 2008

2009

2013

Source: Booth CM et al. Perioperative chemotherapy for bladder cancer in the general population: Are practice patterns finally changing? Urol Oncol.

2017; published online ahead of print.

CN for Metastatic RCC May Decrease Mortality Risk C

ytoreductive nephrectomy (CN) for metastatic non-clear cell renal cell carcinoma (RCC) may decrease cancer-specific mortality (CSM).

In a study of 851 patients (median ae 62 years) with metastatic non-clear cell RCC, researchers found that patients who underwent cytoreductive nephrectomy had a significant 62% decreased risk of CSM than those who did not, according to results published online ahead of print in European Urology Focus. The 2-year cumulative CSM rate was 52.6% for those who underwent cytoreductive nephrectomy group versus 77.7% for those who did not. The investigators observed a survival benefit of cytoreductive nephrectomy across histologic subtypes (papillary, chromophobe, collecting duct carcinoma). Among contemporary patients (those diagnosed during 2010–2014), cytoreductive nephrectomy was associated with a 68% decreased risk of CSM.

Interdialytic Weight Gain Associated With Sleep Apnea S

ignificant interdialytic weight gain in patients on hemodialysis (HD) is associated with obstructive sleep apnea (OSA), Brazilian investigators reported online ahead of print in Sleep and Breathing.

In a study of 55 HD patients (49% male) with low cardiovascular risk, Rebeca R. Harmon, MD, of the University of São Paulo Medical School Hospital, and colleagues found that patients with OSA had a significantly greater proportion of those with an interdialytic weight gain greater than 2 kg compared with those without OSA (96% vs 55%).

In addition, patients with OSA had significantly greater left ventricular (LV) posterior wall thickness (11.3 vs 10.0 mm) and LV diastolic diameter (53 vs 48 mm). On multivariate analysis, interdialytic weight gain greater than 2 kg and LV diastolic diameter were independently associated with OSA. After a median follow-up of 45 months, OSA was associated with a significantly higher incidence of cardiovascular events (28% vs 7%).

BT Alone May Be Sufficient For More Risky PCa Cases B

rachytherapy (BT) alone may be sufficient for treating unfavorable intermediate-risk prostate cancer (PCa), according to study findings published online ahead of print in Urologic Oncology.

BT alone is a well-established treatment modality for favorable intermediate risk (FIR) PCa, but trimodal therapy consisting of BT, androgen-deprivation therapy (ADT), and external beam radiation therapy (EBRT) often is recommended for patients with unfavorable intermediate-risk (UIR) PCa, Martin T. King, MD, from Dana-Farber Cancer Institute and Brigham and Women’s Hospital in Boston, and colleagues explained. In a study of 3723 patients with FIR and UIR PCa who received BT from 1997 to 2013, the FIR and UIR cohorts had median follow-up periods of 7.7 and 7.8 years, respectively. In both cohorts, the investigators observed no difference in PCa-specific mortality between BT alone and BT plus ADT and/or EBRT supplemental therapy.

12 Renal & Urology News

JANUARY/ FEBRUARY 2018 www.renalandurologynews.com

PCa Is More Common in Shift Workers A NEW META-ANALYSIS confirms that shift workers have increased risks for developing prostate cancer (PCa) and provides some additional insight.

Zuxun Lu, MD, of Huazhong University of Science and Technology in China, and his

Survival better with RC continued from page 1

(NCDB, 2004–2013), included 8379 MIBC patients. Of these, 6606 underwent RC and 1773 had CRT (defined as a radiation dose of 40 Gy or higher and chemotherapy within 90 days of radiation therapy. CRT patients were older than RC patients (77 vs 67 years).

Dr Ritch told Renal & Urology News that their definition of CRT was “somewhat generalized” due to the lack of specific criteria in the NCDB, and was not based on a standard protocol with respect to radiation delivery and ­dosage or the type of chemotherapy agent.

“Therefore, it is possible that a specific CRT or trimodality therapy protocol may be comparable to RC in terms of survival,” he said.

The investigators propensity score matched 1683 patients in each group.

The groups were similarly matched with respect to age, gender, race, income, Charlson-Deyo score, clinical T stage, grade, and histologic type. The matched cohort had a median age of 76 years.

In both groups, 66% of patients were Charlson-Deyo score 0. In the matched CRT cohort, 26 patients (2%) underwent RC within 2 years following treatment.

Although CRT is not usually considered standard of care for MIBC,

emerging data support bladder preservation, according to Dr Ritch and his colleagues. They cited a pooled analysis published in the Journal of Clinical Oncology (2014;32:3801-3809) showing that patients with MIBC who underwent CRT had 5- and 10-year OS rates of 57% and 36%, respectively.

Dr Ritch’s team identified CharlsonDeyo score and clinical stage as significant predictors of OS in the matched cohort. Patients with a Charlson-Deyo score of 2 or more had a 48% increased risk of death compared with a score of 0. Patients with cT3-4 tumors had a 45% increased risk of death compared with those who had cT2 tumors. n

­ alance, electrolytes, and acid-base stab tus,” the investigators wrote. With earlier initiation, however, patients who might have recovered without RRT would be exposed to the risks associated with RRT and treatment-related complications.

“Our findings do not support that early RRT initiation is superior to late initiation,” Dr Christiansen and his colleagues concluded. “Although early RRT was associated with increased short-term mortality, we found no association between timing and long-term outcomes. This study extends current knowledge on time of RRT and shortterm mortality by providing estimates

of the impact on long-term mortality and risk of CKD and ESRD.” Previous meta-analyses of primarily observational studies have found early RRT initiation to be associated with decreased short-term mortality compared with late RRT initiation, but most of the included studies had methodological limitations, such as small sample sizes or inadequate control of confounders, the authors wrote.

Dr Christiansen’s team said that, to their knowledge, only 2 observational studies have evaluated mortality beyond 90 days, and none have examined the impact of timing of RRT on CKD and ESRD risk. n

Prostate Cancer and Prostatic Diseases.

The authors commented that, given the anti-inflammatory, anti-proliferative, and antioxidant properties of HDL, it is unclear why high HDL would be associated with an increased risk of PCa. “Our findings demonstrate an association between high serum cholesterol and HDL and increased risk of high-grade prostate cancer in a setting where trial-

that increased serum cholesterol levels may be associated with a higher prostate cancer risk.”

Previous studies supporting a link between cholesterol and high-risk PCa include an analysis of the placebo arm of the Prostate Cancer Prevention Trial (PCPT), which demonstrated a reduced risk of high-grade PCa among men with lower cholesterol levels. Further, in a study of 55,875 patients at the Veterans Affairs New England Healthcare System, researchers found that, compared with men taking antihypertensive medications, men taking statins had a 31%, 14%, and 60% decreased risk of being diagnosed with any PCa, low-risk PCa, and high-risk PCa, respectively, according to a report in the Journal of the National Cancer Institute (2011;103;885-892).

In addition, the highest quartile of total cholesterol at baseline was associated with a 45% increased risk of total PCa and 3-fold increased risk of high-grade PCa. The highest quartile of HDL at baseline was associated with a 45% increased risk of total PCa and nearly 2.6-fold increased risk of highgrade PCa. n

colleagues reviewed 15 studies published 2002 to 2017 including 2,546,822 men, of whom 10,715 developed PCa. According to pooled results published online in Carcinogenesis, shift workers had a significant 23% higher risk of PCa than those who had never performed shift work. The investigators found a nonlinear relationship between longer shift duration and greater PCa risk. Results were adjusted for age, smoking status, education, body mass index, physical activity, and area of residence.

Included studies were conducted in Europe, the United States,

Early vs late RRT for AKI

continued from page 1

these differences in long-term outcomes were statistically significant.

The median time from ICU admission to RRT initiation was 18.9 hours in the early RRT group compared with 32.8 hours in the late RRT group. The investigators defined AKI stage using Kidney Disease: Improving Global Outcomes (KDIGO) criteria.

Noting that the optimal time to initiate RRT for AKI remains unclear, the authors said there “is a theoretical rationale for early initiation of RRT, such as improved control of fluid

Canada, Japan, and China. A subgroup analysis found that Asian shift workers had nearly twice the risk of PCa compared with those from Western countries.

Investigators categorized shift work rotating, night, evening, or mixed. Rotating shift schedules -- which might include a day shift followed by a night shift, for example – had the most association with PCa risk. The investigators explained that rotating schedules force shift workers to adjust their body functions to their on-duty periods, thereby disrupting their sleep pattern.

Possible biologic mechanisms linking shift work in general to PCa include disruption of circadian rhythms, decreased melatonin (a hormone that has antioxidant, anti-mitosis, anti-angiogenesis, and immune effects that might protect from cancer), and impaired vitamin D synthesis due to reduced sunlight exposure. n

Cholesterol, PCa link continued from page 1

The ­investigators found no association between total serum cholesterol and overall or low-grade PCa and between LDL cholesterol and the risk of any PCa. The new study provides “yet one more reason for people to watch their cholesterol and dovetails with some data that statins may have benefits for prostate cancer,” Dr Freedland told Renal & Urology News.

Unlike previous research that found the same association, the new study focused on patients who underwent trial-mandated prostate biopsies independent of PSA, thus eliminating a potential source of bias, according to Dr Freedland’s team. The REDUCE study was a randomized trial that enrolled men with elevated PSA and a negative baseline prostate biopsy. Men underwent 2- and 4-year trial-mandated prostate biopsies.

Each 10 mg/dL increment in total serum cholesterol was associated with a significant 5% increased odds of a diagnosis of high-grade PCa, Dr Freedland and his colleagues reported online in

Elevated total and HDL cholesterol increase the risk of high-grade PCa. mandated biopsies ensured complete cancer ascertainment,” Dr Freedland and his colleagues wrote. “These data support a role for cholesterol, a modifiable risk factor, in aggressive prostate cancer.”

Dr. Freedland’s team explained that PCa is unique in its dependence on androgens for growth. “Cholesterol is the precursor for androgen synthesis by the prostate, leading to the hypothesis

www.renalandurologynews.com JANUARY/ FEBRUARY 2018

Novel 3D Printed Prostates Could Aid Preop Planning New technique uses silicone-based polymer inks to create models ­ odels are ­typically made of hard plasm tic. His team, however, has developed a unique 3D printer that uses customized silicone-based polymer inks, which were developed by carefully studying the mechanical properties of actual prostate tissue. They contend that their 3D printed prostate could be a game changer for organ models. One of the coauthors, Ghazaleh Haghiashtiani,

© IMAGE COURTESY OF MICHAEL C. MCALPINE, PHD.

BY JOHN SCHIESZER RESEARCHERS HAVE developed a new technique for 3D printing patientspecific prostate glands using polymers that accurately model a prostate’s dimensions and physical properties while also providing quantitative tactile feedback. The new model, developed by investigators at the University of Minnesota (UMN) Twin Cities and

Researchers have developed a way to create 3D printed patient-specific prostate models that have the tactile sensation, pliability, and texture of a real prostate.

described in an article published online ahead of print in Advanced Materials Technologies, could enable better preoperative planning and rehearsal that may help improve surgical outcomes in men with prostate cancer (PCa).

“Some preliminary clinical rehearsals, including suturing and endoscopic manipulations, have been performed by medical professionals on these organ models,” said first author Kaiyan Qiu, PhD, a postdoctoral scientist in the department of mechanical engineering. “We foresee that with some improvements to the process, this could be used as an integrated tool for diagnosis and surgical rehearsal as well as for training medical students, and educating patients.”

Possible game changer Aided by magnetic resonance imaging, mechanical engineers and medical doctors in a special collaboration created a 3D printed prostate model that has the same tactile sensation, pliability, and texture as the real gland. Principal investigator Michael C. McAlpine, PhD, Associate Professor of Mechanical Engineering, said 3D printed organ

also in the department of mechanical engineering, said previous 3D printed organ models have been anatomically correct, but they lacked precise mimicry of the physical properties of real tissue.

Haghiashtiani said this has hindered their ability to accurately predict and replicate organ physical behaviors, such as deformation and reaction force during surgical handling.

“In this work, customized polymeric materials have been developed that have properties closely matching the real prostate tissue in terms of static and dynamic mechanical properties, hardness and optical characteristics,” Haghiashtiani told Renal & Urology News. “The organ models in this work include integrated sensors that provide quantitative electrical feedback to the applied mechanical stimulation.”

Haghiashtiani said this electrical feedback enables physicians to quantify and control the force ranges they apply to the organ during preoperative rehearsal and training. This may help lower the chance of adversely affecting healthy tissue, subsequently lowering the risk of urinary problems and erectile dysfunction.

When the prostate model is touched, the

sensors instantly send a visual readout of how much pressure is applied, showing surgeons how hard they are pressing on the model and whether the amount of pressure applied is appropriate or could damage healthy tissue.

Real-time feedback Dr Qiu said the ability to have quantitative, real-time feedback could change how surgeons think about personalized medicine and preoperative practice. “The combination of 3D printing process along with customizable tissuemimicking materials provide a platform for creating real life, patient-specific organ models,” he said. “This could directly enhance their performance in the actual surgery, and thus could decrease the rate of errors and complications during the actual surgery and possibly improve morbidity or mortality.”

In the future, even more complicated organ models could be developed for treating other tumor types, including renal cell carcinoma, by using multiple inks to mimic different tissue properties. Eventually it may even be possible to create 3D organs for transplantation, according to the researchers.

Matthew J. Resnick, MD, Assistant Professor of Urologic Surgery and Health Policy at Vanderbilt University Medical Center in Nashville, Tennessee, said it is too early to know how helpful these models will be in terms of morbidity and mortality. While 3D prostate models may facilitate development of patientspecific surgical plans, important questions remain regarding whether these plans will translate into improvements in either oncologic or functional outcomes, he said. Dr Resnick said it is important that this technology is not oversold.

“It is possible that a 3D prostate model may offer insights surrounding the precise location and extent of disease, and these insights may, at an individual patient level, mediate surgical decision-making, surrounding the extent of nerve-sparing,” Dr Resnick said.

“Nonetheless, it will be critically important to rigorously evaluate the impact of these models in diverse populations to characterize the extent to which the use of such models truly map to measureable improvements in outcomes.” n

Renal & Urology News 15

Cystatin C, AKI Linked, Study Finds SERUM CYSTATIN C levels are strongly associated with development of acute kidney injury (AKI) and short-term prognosis among coronary care unit (CCU) patients, according to a recent study published in Kidney & Blood Pressure Research (2017;42:961-973).

In a prospective, observational study of 412 CCU patients, Yugang Hu, MD, and colleagues at Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China, found that patients in the highest quartile of serum cystatin C (greater than 1.69 mg/L) had a significant 9.6-fold increased risk of incident AKI compared with those in the lowest quartile (less than 0.93 mg/L) in adjusted analyses.

AKI, which was defined using KDIGO (Kidney Disease: Improving Global Outcomes) criteria, developed in 130 patients (31.6%). Among patients with pre-existing chronic kidney disease (CKD), those in the highest quartile of serum cystatin C (greater than 2.86 mg/L) had a 27-fold increased risk of incidence AKI compared with

Elevated cystatin C levels increase acute kidney injury risk in CCU patients. those in the lowest quartile (less than 1.30 mg/L). Among patients without pre-existing CKD, those in the highest quartile of cystatin C (greater than 1.27 mg/L) had a 4.7-fold higher risk of incidence AKI than those in the lowest quartile (less than 0.89 mg/L).

After a median 19.8 month followup, 112 patients (27.2%) died within 2 years after admission. Serum cystatin C independently predicted the risk of 2-year mortality, rehospitalization, and renal recovery failure. A serum cystatin C level of 1.255 mg/L or higher on the first day of admission was associated with a significant 3-fold increased risk of mortality and 1.8-fold increase risk of rehospitalization at 2 years.

“If confirmed further, [serum cystatin C] may provide a unique opportunity to impact dramatically the management of AKI by delivering diagnostic, severity, and prognostic information at an early time-point following a renal insult,” the authors concluded. n

www.renalandurologynews.com JANUARY/ FEBRUARY 2018

Renal & Urology News 19

Optimal PCa Salvage Therapy Unclear Definitive comparative effectiveness data are lacking for how best to treat radiorecurrent disease

BY JOHN SCHIESZER WITH NO DEFINITIVE efficacy data to guide them, surgeons must consider a number of factors when deciding whether salvage prostatectomy or salvage cryotherapy is the optimal treatment for patients who experience recurrence of prostate cancer (PCa) following primary radiation therapy for the disease.

Decision based on patient factors Currently, the decision to perform roboticassisted laparoscopic pros­ta­tec­to­my (RALP) or cryother­a­py is based in large measure on a Gerald L. Andriole, MD patient’s preferences and tumor characteristics, as well as age and comorbidities, according to Gerald L. Andriole, MD, Chief of Urologic Surgery and vice-chair of the department of surgery at Washington University School of Medicine and the Siteman Cancer Center, St. Louis, Missouri. “Generally, the youngest, healthiest men would seem to benefit most from surgery to remove the prostate,” Dr Andriole said.

Prostate removal, either by open, laparoscopic, or robotic-assisted approaches, is apt to provide better local control and cancer outcomes than cryotherapy, he said. “This is likely as

cryotherapy may be incomplete and some residual tumor may be left within the prostate,” Dr Andriole told Renal & Urology News. “Also, prostate removal may identify and control small amounts of cancer that are outside of the prostate, such as in lymph nodes and or the seminal vesicles.” This generally is not possible with cryotherapy, he added.

Individualized treatment needed Level One com­parative data are lacking for salvage therapies, with no clear winner at this point, said Kristen R. Scarpato, MD, MPH, Assistant Professor of Kristen R. Scarpato, MD, MPH Urologic Surgery at Vanderbilt Uni­versity Medical Center in Nashville, Tennessee. Retrospective data and single institution series indicate that both modalities are generally safe and oncologically effective.

“Treatment needs to be individualized to the patient considering his comorbidities, disease parameters, and preferences,” Dr Scarpato said.

“Choice also largely depends on physician experience. Currently, I think that risks are limited and benefits are maximized by carefully selecting appropriate patients and limiting salvage procedures to experienced centers of excellence.”

Salvage RALP offers excellent visualization of the posterior plane between the rectum and the prostate, where the normal tissue planes have often been obliterated by radiation, she said. “Data suggest reasonable oncologic efficacy and minimal blood loss and hospital stay, with an acceptable risk profile,” Dr Scarpato said. “Furthermore, pathologic data are obtained at the time of prostatectomy. Salvage cryotherapy has also been shown to be safe and efficacious and has the advantage of being less invasive.”

Cryotherapy has improved Aaron Katz, MD, Chairman of Ur­ol­ogy at New York University Winthrop Uni­ versity Hospital in Mineola, New York, said that with respect to overall cancer Aaron Katz, MD control, no study has ever demonstrated that salvage prostatectomy provides a better outcome. Salvage cryotherapy, however, may significantly delay the use of androgen-deprivation therapy, he said.

“I’ve done salvage cryotherapy for over 20 years,” Dr Katz said. “The technology has improved. There is no doubt that the quality of life [of patients who undergo] salvage c­ ryotherapy is significantly better than those patients who have salvage prostatectomy.”

Salvage cryotherapy only takes about an hour, and it does not result in blood loss or need for transfusions, he said.

In select patients, salvage prostatectomy may be beneficial, but, overall, in patients who fail radiotherapy without evidence of metastatic disease, salvage cryotherapy is the optimal therapy, Dr Katz said.

Advantages and disadvantages Julio Pow-Sang, MD, Chair of Geni­to­urinary On­col­ ogy at Moffitt Cancer Center in Tampa, Florida, commented that a major benefit of salvage RALP is that patients Julio Pow-Sang, MD are cured if their tumors are localized. A disadvantage of the procedure is that it is a more complicated procedure than cryotherapy, he said. “Few centers around the country perform it. We do,” Dr PowSang said.

Salvage cryotherapy is associated with a lower rate of urinary incontinence than RALP: about 5% versus 10%, Dr Pow-Sang said. Additionally, salvage cryotherapy is minimally invasive and usually does not require a hospital stay. A disadvantage with salvage cryotherapy is that prostate tissue remains, and there is a “risk of another recurrence of about 50%,” Dr PowSang said. n

MRI Predicts PCa Salvage Radiotherapy Outcomes MULTIPARAMETRIC pelvic magnetic resonance imaging (mpMRI) can improve pre-

than positive mpMRI (39% vs 12% and 16% vs 2%, respectively) at 4 years after sXRT,

dictions of salvage radiotherapy (sXRT) outcomes following radical prostatectomy,

Dr Karnes’ group reported. In addition, among patients with a PSA of 0.5 ng/mL or

according to a new study.

less, the addition of mpMRI to a propensity score created using variables from the

For patients with pre-sXRT PSA levels of 0.5 ng/mL or less, negative mpMRI find-

original Stephenson nomogram improved the c-statistic from 0.71 to 0.77 for PSA

ings independently predict an increased likelihood of PSA recurrence and metasta-

recurrence and from 0.66 to 0.77 for metastasis. For patients with a pre-salvage PSA

sis after sXRT.

level above 5 ng/mL, mpMRI did not predict PSA recurrence or metastasis.

The study, by a team at Mayo Clinic in Rochester, Minnesota, led by R. Jeffrey

The investigators state that the findings validate their hypothesis that a negative

Karnes, MD, included 473 sXRT patients who were evaluated by pelvic mpMRI after

mpMRI in the context of rising post-RP PSA indicates an increased likelihood of a

experiencing biochemical recurrence of prostate cancer following RP. Of these

distant source of that PSA. Although patients with a negative mpMRI had slightly

patients, 204 (57%) had lesions on mpMRI. After excluding nodal/bone lesions, 29%

lower pre-salvage PSA compared with patients who had a positive mpMRI, they

of patients had PSA recurrence and 14% had metastasis at a median follow-up of

had a slightly shorter PSA doubling time (9.4 vs 11.1 months), “which supports the

45 months after salvage radiation, the investigators reported online ahead of print

hypothesis that there is a higher risk of occult micrometastatic disease for MRI-

in European Urology.

negative patients.”

Among patients with a pre-salvage PSA of 0.5 ng/mL or less, PSA recurrence and metastasis were significantly more likely to occur among patients with a negative

Dr Karnes and his colleagues concluded that pre-sXRT mpMRI “is a valuable adjunct to current clinicopathologic variables used to estimate the success of sXRT.”

20 Renal & Urology News

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Lupus Anticoagulant Increases Calciphylaxis Risk LUPUS anticoagulant and combined thrombophilia are risk factors for the development of calciphylaxis among patients with late-stage chronic kidney disease (CKD), according to a new study.

“Prospective screening for these factors may help identify patients with ­ eveloping CKD at increased risk for d

calciphylaxis who would benefit from tighter metabolic control and increased screening,” a team led by Daniela Kroshinsky, MD, PhD, of Massachusetts General Hospital in Boston, concluded.

The study, published online ahead of print in JAMA Dermatology, ­compared

38 patients with both calciphylaxis and CKD (case patients) and 114 control patients with CKD matched by age, sex, and race. Among all patients, lupus anticoagulant, protein C deficiency, and combined thrombophilias occurred significantly more frequently in case patients than in controls (48%

vs 5%, 50% vs 8%, and 62% vs 31%, respectively). In a subgroup analysis of patients with stage 5 CKD, only lupus anticoagulant and combined thrombophilia were significantly associated with calciphylaxis. These conditions occurred in 53% and 63% of case patients, respectively, compared with 0% and 8% in the control group. In a subgroup analysis of patients not exposed to warfarin, only lupus anticoagulant and protein C deficiency were significantly associated with calciphylaxis. Lupus anticoagulant and protein C deficiency were present in 50% and 46% of case patients, respectively, compared with only 6% and 0% of controls.

Link found even in patients with severe renal dysfunction not using warfarin.

“Overall, these results indicate that [the] presence of lupus anticoagulant is strongly associated with the development of calciphylaxis, even in individuals with severe renal dysfunction who are not using warfarin,” Dr Kroshinsky and her collaborators wrote.

The authors noted that these data “may provide insight for improved prevention and treatment of calciphylaxis, possibly by better managing thombophilic states in appropriate patients.”

In a recent paper published in the Journal of the American Society of Nephrology (2017;28:1717-1722), a team led by Sagar U. Nigwekar, MD, also from Massachusetts General Hospital, reported that vitamin K deficiency may have a role in the development of calciphylaxis.

The vitamin is an essential cofactor on which gamma-glutamylcarboxylase depends to convert inactive uncarboxylated matrix gla protein (ucMGP) to its active carboxylated form (cMGP), a potent inhibitor of vascular calcification.

In a study comparing 20 hemodialysis (HD) patients with calciphylaxis (cases) and a group of 20 HD patients without calciphylaxis matched by age, sex, race, and warfarin use (controls), Dr Nigwekar and his colleagues found that the fraction of total MGP that was carboxylated was significantly lower in cases than controls (0.58 vs 0.69). Each 0.1 unit reduction in relative cMGP concentration was associated with a greater than 2-fold increased risk of calciphylaxis. n

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Renal & Urology News 21

Incidence of Various Cancers Lower in Warfarin Users WARFARIN USE is associated with a lower incidence of various malignancies, including prostate and breast cancer (PCa), according to a large population-based cohort study. The association between warfarin use and lower cancer incidence was stronger among individuals with atrial fibrillation or atrial flutter.

In a study that used the Norwegian National Registry coupled with the Norwegian Prescription Database and Cancer Registry of Norway, warfarin users had a significant 16% lower incidence of cancer overall compared with nonusers, after adjusting for age and sex, a team led by James B. Lorens, PhD, of the University of Bergen in Norway, reported in JAMA Internal Medicine (2017;177:1774-1780). Warfarin use was associated with a significant 31% lower incidence of PCa compared with nonuse. Warfarin users had a significant 20% and 10% lower incidence of lung and breast cancer, respectively.

The study found no significant association between warfarin use and colon cancer in the overall cohort.

Researchers report a lower incidence of prostate, lung, and breast cancer.

In a subgroup analysis of patients with atrial fibrillation or atrial flutter, warfarin use was associated with a significant 38% lower risk of all cancers and a significant 40%, 61%, 28%, and 29% lower risk of prostate, lung, breast, and colon cancer, respectively, compared with nonuse.

“Our data indicate that warfarin provides a possible cancer protection, a finding that may have important implications for choosing medications for patients who need anticoagulation,” the authors concluded.

The investigators noted that the challenges of warfarin dosing that necessitate regular monitoring have fueled a transition to newer oral anticoagulants.

“An unintended consequence of this switch to new oral anticoagulants may be an increased incidence of cancer, which is an important consideration for public health,” they wrote.

The study cohort consisted of 1,256,725 individuals (48.3% male, 51.7% female), of whom 92,942 (7.4%) were warfarin users. The warfarin

group included 33,313 individuals with atrial fibrillation or atrial flutter.

Dr Lorens and colleagues stated that “the observed association between warfarin use and lower cancer incidence is likely due in part to an enhanced antitumor immune surveillance of early cancer.”

In a discussion of study limitations, the authors noted that the Norwegian Prescription Database lacks information on medications dispensed in hospitals and nursing homes, and these missing data could have led to the systematic misclassification of some individuals as nonusers. Dr Lorens’ team

also acknowledged that they did not have access to prescription information before 2004. “Thus, individuals may have used warfarin longer than the time registered, or warfarin therapy may have been discontinued prior to 2004 and users were misclassified as nonusers.” n

22 Renal & Urology News

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Kidney Failure Associated With Low Albumin Levels LOW SERUM albumin levels are independently associated with an increased risk of end-stage renal disease (ESRD), according to a new study. The association is independent of chronic kidney disease risk factors, including baseline estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (ACR).

In a study of community-dwelling adults, ESRD was 61% and 69% more likely to develop among individuals with serum albumin levels in the first and second quartiles (below 4.0 and 4.0–4.1 g/dL), respectively, compared with those who had levels in the fourth quartile (4.4 g/dL or higher) in a fully

adjusted model, Carl P. Walther, MD, of the Baylor College of Medicine in Houston, and colleagues reported online ahead of print in Nephrology Dialysis Transplantation. Each 0.33 g/ dL decrease in serum albumin was associated with a 16% increased risk T:6.875” of ESRD.

The ­researchers adjusted for age, sex, race, baseline eGFR, body mass index, systolic blood pressure, antihypertensive drug use, smoking status, various laboratory measures and comorbidities, and urine ACR. “To our knowledge, this is the first study to demonstrate an association

T:9.875”

SUTT17CDNY0411_ADJ_Brief_Summary_Day_1_Jrnl_Ad_A_size_r10_FSU.indd 1

12/5/17 4:15 PM

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between serum albumin concentrations and ESRD while accounting for urine ACR in a community-dwelling adult population,” Dr Walther’s team reported.

The association between serum albumin level and incident ESRD was more pronounced in the subgroup of participants with a baseline eGFR of 60 mL/min/1.73 m2 or higher, the investigators reported. In this subgroup, the first and second quartiles of

serum albumin were associated with a 7-fold and 4-fold increased risk of ESRD, respectively, compared with the fourth quartile in a fully adjusted model. Each 0.33 g/dL decrease in serum albumin was associated with a 61% increased risk of ESRD. By comparison, among individuals with an eGFR below 60 mL/min/1.73 m2, the first and second quartiles of T:6.875” serum albumin were associated with an

11% and 39% increased risk of ESRD, respectively, compared with the fourth quartile, and each 0.33 g/dL decrease in serum albumin was associated with a 14% increased risk of ESRD. The study population consisted of 19,633 individuals who participated in the REGARDS (Reasons for Geographic and Racial Differences in Stroke) study, a US prospective, population-based cohort study of black and white adults

aged 45 years or older. Dr Walther’s team determined eGFR using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) combined creatinine-cystatin C equation. They identified incident ESRD cases using the US Renal Data System.

Dr Walther and his colleagues acknowledged some study limitations, such as exclusion of individuals of races other than white and black. n

T:9.875”

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24 Renal & Urology News

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7-Month PSA in Treated mHSPC Is Prognostic

BY JODY A. CHARNOW PATIENTS with metastatic hormonesensitive prostate cancer (mHSPC) who achieve a PSA level of 0.2 ng/mL or less at 7 months after initiation of androgen deprivation therapy (ADT), with or without docetaxel, have longer overall survival, according to a new study.

The 719 mHSPC patients in the current analysis had participated in the CHAARTED (Chemohormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer) study, a phase III, open-label trial in which investigators randomly T:6.875” assigned patients

to receive either ADT alone or ADT plus 6 cycles of docetaxel. The cohort included 358 patient treated with ADT plus docetaxel and 361 treated with ADT alone.

The cohort had a median follow-up of 23.1 months starting 7 months after ADT initiation. Overall survival across

all patients was significantly longer if the 7-month PSA level was 0.2 ng/mL or less compared with a level greater than 4 ng/mL (median 60.4 vs 22.2 months) according to Lauren C. Harshman, MD, of the Dana-Farber Cancer Institute in Boston, and colleagues who reported online ahead of print in the Journal of Clinical Oncology. On multivariable analysis, a 7-month PSA level of 0.2 ng/ mL or less was associated with an 82% decreased risk of death compared with a 7-month PSA level above 4 ng/mL. “PSA is attractive as a much earlier biomarker of improved clinical outcomes than overall survival, but requires further prospective study to prove it a true surrogate,” Dr Harshman told Renal & Urology News. “Our results also highlight outstanding questions regarding intensification of therapy and whether patients who don’t experience this ideal PSA should intensify their current regimen.”

ADT recipients who achieved PSA levels of 0.2 ng/mL or less had the best survival.

T:9.875”

For example, she noted, if a patient is on ADT alone, should docetaxel be added to try to induce a PSA level of 0.2 ng/mL? Patients who received ADT alone and achieved a 7-month PSA of 0.2 ng/mL or less had the best survival (median 72.8 months). Median survival was the worst at 21.6 months among ADT-only recipients whose 7-month PSA was above 4 ng/mL. Patients receiving ADT and docetaxel who achieved a 7-month PSA level of 0.2 ng/mL or less had a significantly greater median survival of 60.4 months compared to those whose 7-month PSA level remained above 4 at 25.2 months.

On multivariable analysis, after 7 months of ADT, the risk of death was 50% lower among those with lowvolume versus high-volume disease.

Compared with ADT alone, ADT plus docetaxel was associated with approximately 2.6-fold increased odds of achieving a PSA of 0.2 ng/mL or less at 7 months.

In their acknowledgement of study limitations, the authors noted, “It is likely that the CHAARTED study as a whole was subject to selection bias in terms of which patients were referred for a study that included chemotherapy.” n

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Renal & Urology News 25

PCa Gene Testing Guidelines Issued Clinicians need to ask about cancers among members of the maternal and paternal sides of a family

BY JOHN SCHIESZER AN INTERNATIONAL expert panel has developed a comprehensive, multidisciplinary consensus statement for the genetic evaluation of inherited prostate cancer (PCa) in the multigene testing era, according to a new report.

The goal of the consensus statement, which was published online ahead of print in the Journal of Clinical Oncology, is to provide a focused and balanced clinical approach to genetic testing, genetic counseling, and geneticallyinformed screening and management for men with PCa relevant to urologists, oncologists, primary care providers, clinical cancer genetics specialists, and genetic counselors.

“Urologists are often on the front lines of diagnosis and treatment of prostate cancer,” said lead author Veda N. Giri, MD, Director of Cancer Risk Assessment and Clinical Cancer Genetics in the Department of Medical Oncology at Sidney Kimmel Cancer Center at Thomas Jefferson University in Philadelphia, told Renal & Urology News. “These consensus recommendations point to the need to obtain family history information regarding cancers in males and female relatives on the maternal and paternal sides of the family when evaluating and treating men with prostate cancer.”

With this information, urologists could assess whether men should be referred for genetic counseling and testing. These cancers include prostate, breast, ovarian, colorectal, uterine, and pancreatic cancers and melanoma.

A man’s relatives may benefit A genetic test could reveal mutations that may impact a son, daughter, sister, brother or other relatives and reveal higher risks of cancer across a family.

“As data emerge, genetic testing for inherited mutations may increasingly be used in the conversation that urologists have with patients regarding management of localized prostate cancer, and therefore there is a need for increased collaboration between urologists and cancer genetic specialists,” Dr Giri said.

Up to 15% of prostate malignancies may be inherited, and at least some of the genes that confer inherited risk are known and testable.

Guidelines for genetic counseling and genetic testing for PCa are limited and focus only on testing of

BRCA1 and BRCA 2, the consensus statement authors pointed out. They noted that National Comprehensive Cancer Network (NCCN) Genetic Familial High-Risk Assessment: Breast and Ovarian (Version 2.2017) guidelines, published in the Journal of the National Comprehensive Cancer Network (2017;15:9-20), address testing BRCA1 and BRCA2 for men with a personal history of PCa limited to Gleason 7 or higher with specific family history features, or metastatic prostate cancer.

The NCCN guidelines, however, do not specifically address other genes now available for testing via multigene panels, some of which are implicated in PCa predisposition.

Personalized therapy possible Senior author Leonard Gomella, MD, Chair of Urology and Clinical Director of the Sidney Kimmel Cancer Center Network at Thomas Jefferson University, said the consensus panel was convened to fill a significant gap in current guidelines. “Genetic testing for inherited PCa may help ­optimize

As much as 15% of prostate cancers may be inherited, lead author says and personalize treatment, but it also reveals information that can impact entire families and older and younger generations,” Dr Gomella said.

Commercially available genetic tests for inherited PCa risk can cover from 10 to 14 genes that can inform clinical decision making.

The new guidelines are a product of the Philadelphia Prostate Cancer Consensus Conference 2017 hosted

by Sidney Kimmel Cancer Center.

Participants included specialists in urology, clinical cancer genetics and genetic counseling, medical and radiation oncology, primary care, and researchers. Gynecologic oncology and breast cancer specialists, patient advocates, and bioethicists also participated.

“Without this consensus review, it is difficult to capture who should be referred for genetic counseling and testing,” Dr Gomella said. It is important to determine who may need to

Veda N. Giri, MD

be ­monitored more closely and which men may need to start PCa screenings earlier than recommended in general screening guidelines.

PCa patients with inherited mutations in the BRCA2, BRCA1, and ATM genes may respond to poly ADP ribose polymerase (PARP) inhibitors, especially if their disease has metastasized and is resistant to initial treatments, according to the guidelines. The consensus panel agreed with other national organizations that men with metastatic PCa should be considered for genetic counseling and genetic testing to determine if their PCa was inherited.

New recommendations The consensus statement also expanded considerations of PCa screening and management of early-stage disease based on genetic test results, which was a gap in current guidelines. The expert panel arrived at a moderate consensus for BRCA2 testing in early-stage management discussion, but reached a stronger consensus for this testing in the high-risk/advanced and metastatic setting. Panel members were in moderate agreement with respect to testing all men with metastatic castration-resistant disease, regardless of family history.

Areas in critical need of further research identified by the consensus panel include genetic testing in AfricanAmerican men, greater understanding of the genetic basis for aggressive prostate cancer, genetically-informed management and outcomes in early-stage disease, and the economic impact of genetic testing for PCa. Dr Gomella said this new set of recommendations may help lower morbidity and mortality among PCa patients.

“By identifying family members of the potential for inherited prostate cancer

Leonard Gomella, MD

risk, screening can be started earlier in life than has been traditionally recommended. Further, these inherited prostate cancer genes appear to identify men who are the best candidates for new targeted drug therapies if the cancer becomes advanced,” Dr Gomella said.

Yair Lotan, MD, Professor and Chief of Urologic Oncology at the University of Texas Southwestern Medical Center in Dallas, said the new recommendations may significantly benefit urologists because this is an area where the literature is evolving or contradictory.

“I think it adds some clarity on which groups need testing and what tests to consider,” Dr Lotan said. “The main point of the guidelines is to identify patients at risk and refer them to genetic counselors for discussion of testing. It also informs on what tests should be considered at this time. The actual tests will likely evolve over time so the current list will likely change in the future.”

Zachary Hamilton, MD, Assistant Professor of Urology at Saint Louis University in Missouri, said the consensus statement fills a previous gap in urologic oncology guidelines. PCa screening guidelines have been evolving and now place more emphasis on selective and informed screening, especially for men at highest risk for aggressive disease.

“While routine genetic testing may not be ready for daily clinical practice, this consensus statement provides expert opinion on how to best incorporate the current knowledge base,” Dr Hamilton said. “With more time and additional research, genetic testing will be adapted into treatment guidelines by major organizations.

Until then, this consensus statement provides a framework for urologists who treat prostate cancer.” n

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n FEATURE

New PCa Grading System Gains Wide Acceptance A 5-tier Gleason grade group system endorsed by the International Society for Urological Pathology in 2014 is now used routinely in pathology reports and patient counseling

F

irst described in a paper published 4 years ago, the new Gleason grade group system for the risk classification of prostate cancer (PCa) is now routinely included in PCa pathology reports and commonly used in counseling patients newly diagnosed with the malignancy.

Stephen J. Freedland, MD, Professor of Surgery and Associate Director for Faculty Development at the Samuel Oschin Comprehensive Cancer Institute at Cedars-Sinai Medical Center in Los Angeles, says his institution regularly includes grade groups in PCa pathology reports. “We still get Gleason scores on our pathology reports, but we also get the new grade group [classifications],” said Dr Freedland, who holds the Warschaw Robertson Law Families Chair in Prostate Cancer. “In talking to patients, I find it much easier to use.” He noted, however, that he still has to explain Gleason scores because patients invariably go online to find PCa information, and the websites they visit typically discuss Gleason scores.

In time, Dr Freedland said, it is likely discussions about Gleason scores with patients will fade away because the new grade group system is much easier to explain, “but we are in a transition period, where we need to explain both.”

The new Gleason grade group system, which is a modification of the original Gleason scoring system, was first described in a 2013 paper in BJU International. In November 2014, participants in an International Society for Urological Pathology (ISUP) consensus conference endorsed the grade group system and proposed its adoption in a 2016 report in the American Journal of Surgical Pathology. In addition to endorsement by ISUP, the World Health

Organization accepted it for inclusion in the 2016 edition of Pathology and Genetics: Tumours of the Urinary System and Male Genital Organs.

The system consists of 5 grade groups that correspond to traditional Gleason scores 6, 3 + 4, 4 + 3, 8, 9, and 10, with grade group 1 indicating the most favorable prognosis and grade group 5 the least favorable. In a 2016 interview with Renal & Urology News, Jonathan I. Epstein, MD, of Johns Hopkins Medical Institutions in Baltimore, who led the team that was the first to propose the new grading system, said the system distills pathologic findings into the key differences in prognosis “that can be intuitive to both patients and clinicians.”

Key features A key feature of the new system is the placement of Gleason score 6 cancers into grade group 1. Another key aspect is the distinction the system makes between

Gleason score 3 + 4 and 4 + 3 cancers, which often are simply called Gleason score 7 disease in discussions with patients but which differ substantially in prognosis. The grade group system separates these cancers into Grade Group 2 and 3, respectively.

Easier to explain to patients “Over the past year, I’ve been utilizing the Gleason grade group system for patient counseling of prostate cancer,” said Zachary Hamilton, MD, an Assistant Professor in the Division of Urology at Saint Louis University School of Medicine in Missouri. The new system is more “patient-friendly,” and it is much easier to describe grade groups of 1 to 5 as opposed to the traditionally used Gleason 6 to 10. “I feel it’s especially helpful for patients to understand low-risk tumors, such as grade group 1, and for delineating the difference between Gleason 3 + 4 vs 4 + 3 as grade groups 2 vs 3.”

The Gleason grade group system, first described in 2013, builds on the original Gleason scoring method for indicating the degree of differentiation of prostate cancer cells.

Pathologists at his institution routinely include the traditional Gleason score and new grade group system in their reports, “but I believe in the next several years most centers will make the transition to the new grade grouping,” Dr Hamilton said.

Elliot M. Paul, MD, a physician partner at Advanced Urology Centers of New York’s Lake Success division, said the pathologists at his practice have started using the Gleason grade group system, and urologists have been pleased with its integration. The traditional Gleason scoring system often confused patients, and it can be difficult to explain to patients that Gleason 6 disease actually is low-risk cancer, despite being rated a score of 6 out of 10. Similarly, explaining the difference between Gleason 3 + 4 and 4 + 3 disease can be complex and time consuming, yet often makes a big difference in terms of prognosis and evaluation, he noted.

“The newer Gleason grade group system has certainly assisted my colleagues and me in patient counseling,” Dr Paul said. “I have spent a lot of time trying to calm patients and their wives after they misunderstood and overestimated the severity of Gleason 6 disease. I now find it a lot easier to explain the safety of active surveillance for many patients with Gleason grade group 1, which saves me time and my patient from unnecessary anxiety. I look forward to the Gleason grade group system being utilized more uniformly by pathologists worldwide, thereby allowing patients and clinicians to communicate more effectively and thus eliminate some of the confusion when explaining pathology results to our patients.”

Pathologists at his practice transitioned to the Gleason grade group

© NATIONAL CANCER INSTITUTE / SCIENCE SOURCE

BY JODY A. CHARNOW

www.renalandurologynews.com JANUARY/ FEBRUARY 2018

Stephen J. Freedland, MD

system more than 2 years ago, but, for now, they also report the Gleason score next to the grade group score.

Sanoj Punnen, MD, Assistant Professor of Urology at the University of Miami’s Miller School of Medicine, reports a similar experience using the grade group system. “We have started using it, and it is much easier to discuss pathology with patients using this system,” Dr Punnen said. “For example, it is difficult to explain to someone with Gleason 6 that their cancer is low grade, when it is scored more than half way up the Gleason scale. Saying your cancer is only grade group 1 is much more interpretable.”

Trying to discuss the difference between Gleason 3 + 4 and 4 + 3 disease can be difficult, “but now we can just say the difference between grade group 2 and 3, which again makes much more sense to patients,” he said.

Some clinicians unconvinced Some clinicians, however, are not impressed with the new system. Scott Eggener, MD, professor of surgery and co-director of the Prostate Cancer Program at the University of Chicago Medical Center, said he still prefers to use the traditional Gleason 6 to 10 scoring because this is what patients will encounter when they go online to research their disease or discuss their cancer with other prostate cancer patients. The grade group system, he said, can be confusing to patients.

Although transitioning to the new grade group system will be slow, “I expect that it will eventually be widely accepted, and it will be the new norm,” he said.

R. Jeffrey Karnes, MD, Associate Professor of Urology at Mayo Clinic in Rochester, Minnesota, said he is not

R. Jeffrey Karnes, MD

convinced the grade group system, which his institution started using this year, is an improvement. The grade group system, he said, is essentially a renaming exercise because Gleason scoring, which has been in use for around half a century, is the basis of the new system. Gleason scoring has been, and continues to be, the most prognostic variable in PCa, especially for patients treated with surgery, he noted. “I did not find the system broken,” Dr Karnes said.

“Perhaps the renaming might make patients understand the grading better in prostate cancer,” said Dr Karnes, chair of the Division of Community

Zachary Hamilton, MD

Urology at Mayo, “but there are many more survivors out there who know and understand the Gleason grading system and might just be confused when told that they have a group 1 [classification].”

Confusion possible The grade group system could lead to loss of specificity and more confusion in pathology reporting, as would be the case with reporting Gleason grade at positive surgical margins, Dr Karnes said. Take, for example, a patient with Gleason 7 cancer. If he has Gleason grade 4 or 3 at a surgical margin, how would a pathologist report that? Or,

PCSM Risk Homogenous in Patients with Grade Group 4 Prostate Cancer Grade group 4 in the new 5-tiered prostate cancer (PCa) risk classification system is homogenous with regard to all-cause and prostate cancer-specific mortality (PCSM) risk, according to a new study published online ahead of print in Pathology & Oncology Research.

Grade group 4 consists of Gleason patterns 4 + 4, 3 + 5, and 5 + 3. Among men in grade group 4, the 60-month PCSM rates for those with 4 + 4 and 3 + 5/5 + 3 disease was 17% and 20%, respectively. In adjusted analyses, patients with 3 + 5 and 5 + 3 disease had no significant difference in all-cause mortality and PCSM risk compared with those who had 4 + 4 disease (reference group).

In addition, compared with the reference group, patients with Gleason 4 + 3 and 9 disease had a 30% decreased and 50% increased PCSM risk, respectively.

The study, by Thomas Chengxuan Lu, MD, of the University of Adelaide in Adelaide, Australia and colleagues, included 4080 men diagnosed with nonmetastatic PCa. The International Society of Urological Pathology (ISUP) and the World Health Organization adopted the 5-tiered risk stratification system in 2014.

Renal & Urology News 27

Elliot M. Paul, MD

just in general for Gleason 7, how does a pathologist now give the percentage of grade 4? That percentage could have an impact on clinical management, he said. Further, tumors containing Gleason grade 5 and 3 are potentially more aggressive that 4 + 4 tumors, but all of these would be classified as Grade Group 4, he said.

Additionally, Dr Karnes pointed out that PCa educational materials available to patients may need to be rewritten, and PCa registries used for research will have to be reworked to reflect the change in how patient risk is classified.

Journals favor the new system Regardless of how urologists and other specialists feel about using the grade group system in clinical practice, those involved in PCa research may have no choice but to embrace it. Editors of major urology and urologic oncology journals (Journal of Urology, Urology, Urologic Oncology, BJU International, European Urology, and International Journal of Radiation Oncology Biology Physics) now require investigators to use the new system in their PCa papers. In an article published in all of those journals, the editors wrote: “The new system provides clearer guidance for pathologists to classify cancers on the basis of gland morphology, and it aligns better with contemporary management including active surveillance. The editors of the major uro-oncology journals believe this is a helpful change for clinicians, researchers, and patients alike and are eager to help this system establish itself in the reporting of pathologic grade.”

Since that publication, other journals, including Prostate Cancer and Prostatic Diseases, have adopted the new system. n

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n SPECIAL FEATURE

Outpatient Transperineal Prostate Biopsy: A Case for Wider Use The approach is associated with fewer infectious complications

BY BENJAMIN T. RISTAU, MD, MHA, AND DAVID Y.T. CHEN, MD

P

rostate cancer (PCa) is the most common non-cutaneous malignancy in men, with 164,690 new cases expected to be diagnosed in the United States alone in 2018.1 Currently, the gold standard for initial PCa detection is the 12-core transrectal ultrasound-guided prostate biopsy (TRUS-B).2 The most pressing concerns with traditional TRUS-B involve the accuracy of making a PCa diagnosis and associated secondary procedure-related complications, including hemorrhage and sepsis.

From a cancer diagnosis standpoint, TRUS-B is imperfect because overdiagnosis of clinically indolent cancers and underdiagnosis of biologically aggressive disease continue to be common events.3,4 The recent application of multiparametric magnetic resonance imaging (MRI) to the prostate to identify areas of greater suspicion, combined with MRI/ultrasound fusion-targeted prostate biopsy, has mitigated some of the problems associated with cancer diagnosis, but issues with infectious complications remain.

Up to 7% of patients who undergo TRUS-B suffer an infectious episode, and sepsis occurs in up to 3%.5 With emerging resistance to antimicrobials— particularly the commonly used fluoroquinolones—the incidence of infection after TRUS-B is expected to rise.6 The transperineal (TP) approach to prostate biopsy has recently been adopted at many centers as an alternative to TRUS-B and may be able to address some of these concerns. For example, TP may improve PCa diagnosis by allowing easier access to sample the entire prostate gland, particularly the anterior prostate.7 Moreover, reported rates of infectious complications associated with TP biopsy are exceedingly low, with ­hospital

Benjamin T. Ristau, MD

a­ dmissions for infection approaching zero in most accounts.8 Together, the potential for improved PCa diagnosis and reduced risk of complications elevates the importance of a structured investigation of the TP approach for prostate biopsy.

Transrectal vs transperineal approach One randomized trial and a metaanalysis have explored differences in

David Y.T. Chen, MD

c­ ancer detection between TRUS-B and TP biopsy (Table 1). Hara and colleagues randomized 226 patients to either TRUS-B or TP approach.9 After randomization, the cohorts were matched regarding patient age, PSA level, prostate volume, PSA density, and DRE findings.

The overall cancer detection rate was similar: 48.3% (58/120) for TRUS-B and 42.1% (53/126) for the TP approach (P = 0.323). However, the authors did

not stratify cancer detection based on contemporary definitions of clinical significance or define possible differences in Gleason grade/Grade Group results.

Of note, in an earlier subgroup analysis of the first 200 patients in the study, Takenaka and colleagues reported that TP biopsy was more sensitive to diagnose transition zone tumors in patients with PSA levels of 4–10 ng/mL (10.7% vs 5.6%, P = 0.045).10 This difference was not reported in a later analysis.

Shen and colleagues performed a systematic review and meta-analysis of 7 studies (2,218 patients) to assess differences in cancer detection rate between TRUS-B and TP biopsy.11 Again, there was no difference in overall PCa detection rate between the TRUS-B (31.4%) and TP (25.7%) approach (P = 0.3).

The lack of difference in PCa detection persisted in subgroup analyses stratified

by PSA level.

Taken together, these studies suggest that the TRUS-B and TP approaches continued on page 30

Table 1. Prostate Cancer Detection and Complications Between TRUS-B and TP biopsy Reference

n

Mean Age (y)

Positive cores (%)

Infection (%)

Bleeding (%)

Hara et al.9

TRUS-B: 120 TP: 126

TRUS-B: 71.1 ± 7.6 TP: 71.0 ± 7.3

TRUS-B: 48.3 TP: 42.1

TRUS-B: 1.7 TP: 0

TRUS-B: 9.2 TP: 10.3

Loeb et al.12

TRUS-B: 9,241

TRUS-B: median 67.6 (54.6 – 76.6)

TRUS-B: 10

TRUS-B: 4.2

TRUS-B: 22 –- 50

Raaikmakers et al.25

TRUS-B: 5,802

TRUS-B: NR

TRUS-B: 22.8

TRUS-B: 3.5

TRUS-B: 22 –- 50

Pepe et al.16

TP: 3000

TP: median 61.8 (40 – 73)

TP: 38.3

TP: 0.7

TP: 31.2

Grummet et al.8

TP: 245

TP: median 61 –- 70

TP: 39

TP: 0

TP: NR

Merrick et al.23

TP: 46

TP: 63.3 ± 9.8

TP: 67.4

TP: 0

TP: NR

Symons et al.26*

TP: 409

TP: 63.3 ± 0.8

TP: 56.7

TP: 3.2

TP: 50.4

TP: transperineal TRUS-B: transrectal ultrasound-guided biopsy NR: not reported *TP saturation biopsy with mean 19.2 ± 0.77 cores

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are equivalent in overall PCa detection rate. A major limitation thus far is a lack of information regarding any possible difference in detection of clinically significant PCa (eg, Grade Group 2 or higher) between the 2 approaches.

TP biopsy under the same outpatient conditions currently used for TRUS-B.

Conclusions

Complications Given the similar PCa detection rate between TRUS-B and TP biopsy, a reduction in procedural risk could justify greater utilization of the TP approach.

To date, randomized, controlled trial data suggest little difference in overall complications between the approaches.9,10 Non-randomized data, however, suggest a reduction in infectious complications with TP biopsy.

The reported risk of any infection after TRUS-B biopsy is 5%–7%, and more severe infections requiring hospitalization range from 1%–3%.5 In the European Randomized Study of Screening for Prostate Cancer, postprocedural fever was reported in 392 patients (4.2%) and resulted in 78 (0.8%) hospital admissions.12 Various strategies have been adopted aiming to reduce infectious complications after TRUS-B, including rectal swab culture-directed antibiotic prophylaxis.5 In a pilot prospective cohort, using a culture-directed antibiotic prophylaxis approach resulted in fewer infectious complications and a cost reduction of $4,500 per avoided infection.13 Given the recognized increasing rates of fluoroquinolone-resistant organisms,14 however, it is reasonable to predict that rates of post-biopsy infectious complications will increase. Moreover, the FDA has recently changed the safety labeling for fluoroquinolones, recommending that they should not be used for uncomplicated urinary tract infections (UTIs) unless there are no appropriate alternatives.15 Thus, appropriate stewardship of antibiotics is of utmost importance.

Infectious complications associated with TP biopsy are less prevalent. In the largest reported series to date (3000 patients), Pepe and Aragona reported post-procedural fever in 17 (0.5%), and UTIs requiring hospitalization in 21 (0.7%).16 Importantly, no patients experienced an infection meeting sepsis criteria. Grummet and colleagues presented a review of patient admissions for sepsis after TP biopsy;8 of 6,609 patients, only 5 (0.076%) cases of sepsis were reported. Given similar cancer detection rates between TRUS-B and TP biopsy and markedly lower risk of infectious complications associated with TP biopsy, the latter may deserve more consideration than it currently enjoys.

FIGURE 1. A surgeon is performing a transperineal prostate biopsy using the PrecisionPointTM Transperineal Access System.

Transperineal technique and patient-reported outcomes One of the major criticisms of the TP biopsy technique is the need for general anesthesia.17 Indeed, the common template-based, TP biopsy approach has been described with the patient under general anesthesia.7,18 For example, the gold standard to which MRI-US fusion targeted prostate biopsy was compared in the PROMIS study was a transperineal, template-based biopsy performed under general anesthesia.7 Similarly, Hansen and colleagues recently reported their experience with MRI-US fusion supported transperineal prostate biopsy using general anesthesia.18 General anesthesia is not mandatory for TP biopsy, however, and procedures under local anesthesia have been reported. Bass and colleagues reported on outpatient TP biopsy in 181 patients.19 Men receive tramadol 100 mg orally and topical 2% diltiazem ointment to relax the anal sphincter 1 hour prior to the procedure. Twenty milliliters of lidocaine-infused gel are inserted into the rectum. The perineal skin is anesthetized with 0.5% bupivacaine and 1:200,000 epinephrine. A peri-prostatic block is then performed transperineally with a 50:50 mixture of 10 mL of 0.5% bupivacaine and 10 mL of 1% lidocaine.

The biopsy procedure is performed after allowing 2 minutes for the local analgesia to take effect.

Further, several variations on local anesthetic techniques have been described including subcutaneous perineal nerve block, pudendal nerve block, periapical triangle block, and prostatic apex block.20 Iremashvili and colleagues completed a randomized controlled trial assessing the tolerability of peri-prostatic block versus peri-prostatic block with

pudendal nerve block.21 Patients receiving the pudendal nerve block reported significantly better pain control throughout probe insertion, biopsy punctures, and at 1 hour after biopsy.

Local anesthetic techniques result in acceptable patient-reported tolerability outcomes. Bass and colleagues reported that 89% of men were “not dissatisfied” with their procedure and would recommend it to others.19 Smith and colleagues assessed the tolerability of outpatient prostate biopsy in 50 consecutive patients using visual analog scales (VAS).22 On a scale from 0-10, in which 0 represents no pain and 10 represents the worst pain imaginable, mean VAS scores for probe insertion (3.08 ± 1.64) local anesthetic injections (3.29 ± 1.64), and biopsies (2.88 ± 1.28) were within acceptable ranges. Similarly, Merrick et al. recorded mean VAS scores for 46 men after instillation of local anesthesia (4.2 ± 1.8) and after outpatient transperineal prostate biopsy (3.0 ± 1.4).23 Thus, it appears that an acceptable patient experience can be provided in the outpatient setting with appropriate expertise.

Traditionally, TP biopsy has been performed using a brachytherapy grid and stepper.19 Free-hand techniques have been reported to eliminate the need for a grid and stepper, although these techniques are somewhat difficult to master.24 A guided TP technique using the recently developed PrecisionPointTM Transperineal Access System (Perineologic, Cumberland, Maryland) has shown some promise in facilitating the transition from a brachytherapy grid and stepper to a free-hand approach that can be more readily performed in the outpatient setting (Figure 1). Early results with this device are encouraging, enabling

Cancer detection rates for TRUS-B and TP prostate biopsy are similar, and either approach can be combined with MRI to enable more accurate targeting of suspicious lesions. A major advantage of the TP approach is a reduction in post-procedural infectious complications. The overall sepsis rate of 0.08% using the TP approach is an order of magnitude lower than the 1%–3% rate seen with TRUS-B. As bacterial resistance patterns emerge, antibiotic stewardship will become increasingly important. Moreover, several outpatient TP biopsy series using local anesthesia alone have recently been reported abrogating the often criticized requirement for general anesthesia. Given lower rates of infectious complications and greater feasibility of an office-based procedure, we expect that TP prostate biopsy will be increasingly adopted as the preferred approach for PCa ­evaluation. n Benjamin T. Ristau, MD, MHA, is an Assistant Professor of Surgery and Urologic Oncology at UConn Health in Farmington, Connecticut, and David Y.T. Chen, MD, is an Associate Professor of Urologic Oncology at Fox Chase Cancer Center in Philadelphia.

REFERENCES 1. Siegel RL, Miller KD, Jemal A: Cancer Statistics, 2018. CA Cancer J Clin, 68: 7-30.

2. Mottet N, Bellmunt J, Bolla M, et al. EAU-ESTRO-SIOG Guidelines on Prostate Cancer. Part 1: Screening, Diagnosis, and Local Treatment with Curative Intent.

Eur Urol 2017;71:618-629.

3. Draisma G, Etzioni R, Tsodikov A, et al. Lead time and overdiagnosis in prostate-specific antigen screening: importance of methods and context.

J Natl Cancer Inst 2009;101:374-383.

4. Epstein JI, Feng Z, Trock BJ, et al. Upgrading and downgrading of prostate cancer from biopsy to radical prostatectomy: incidence and predictive factors using the modified Gleason grading system and factoring in tertiary grades. Eur Urol 2012;61:1019-1024.

5. Liss MA, Ehdaie B, Loeb S, et al. An Update of the American Urological Association White Paper on the Prevention and Treatment of the More Common Complications Related to Prostate Biopsy.

J Urol 2017; published online ahead of print.

6. Feliciano J, Teper E, Ferrandino M, et al. The incidence of fluoroquinolone resistant infections after prostate biopsy--are fluoroquinolones still effective prophylaxis? J Urol 2008;179:952-955.

7. Ahmed HU, El-Shater Bosaily A, Brown LC, et al.

Diagnostic accuracy of multi-parametric MRI and TRUS biopsy in prostate cancer (PROMIS): a paired validating confirmatory study. Lancet 2017;389 (10071):815-822.

8. Grummet JP, Weerakoon M, Huang S, et al. Sepsis and ‘superbugs’: should we favour the transperineal over the transrectal approach for prostate biopsy?

BJU Int 2014;114:384-388.

9. Hara R, Jo Y, Fujii T, et al. Optimal approach for prostate cancer detection as initial biopsy: prospective randomized study comparing transperineal versus transrectal systematic 12-core biopsy. Urology 2008;71:191-195.

10. Takenaka A, Hara R, Ishimura T, et al. A prospective randomized comparison of diagnostic efficacy between transperineal and transrectal 12-core prostate biopsy.

Prostate Cancer Prostatic Dis 2008;11:134-138.

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Renal & Urology News 31

Urologic Cancer Risk Higher in ESRD Patients PATIENTS WITH end-stage renal disease (ESRD) are at increased risk for urologic malignancies, according to a recent systematic review and metaanalysis of 19 observational studies involving 1,931,073 ESRD patients.

ESRD is associated with 6-fold and 4.4fold increased risk of kidney cancer and urothelial cancers, respectively, compared with the absence of ESRD, investigators reported online ahead of print in Nephrology. Urothelial cancers included carcinomas of the bladder, ureters, and renal pelvis. The pooled estimated incidence of kidney cancer and urothelial cancers in ESRD patients were 0.3% and 0.5%, respectively, according to a team led by Panagiotis Kompotiatis, MD, of the Department of Medicine at Mayo Clinic

Transperineal biopsy continued from page 30 11. Shen PF, Zhu YC, Wei WR, et al. The results of transperineal versus transrectal prostate biopsy: a systematic review and meta-analysis. Asian J Androl 2012;14:310-315.

12. Loeb S, van den Heuvel S, Zhu X, et al. Infectious complications and hospital admissions after prostate biopsy in a European randomized trial. Eur Urol 2012;61:1110-1114.

13. Taylor AK, Zembower TR, Nadler RB, et al. Targeted antimicrobial prophylaxis using rectal swab cultures in men undergoing transrectal ultrasound guided prostate biopsy is associated with reduced incidence of postoperative infectious complications and cost of care. J Urol 2012;187:1275-1279.

14. Kandil H, Cramp E, Vaghela T. Trends in antibiotic resistance in urologic practice. Eur Urol Focus 2016;2:363-373.

15. Aschenbrenner DS. The FDA revises boxed warning for fluoroquinolones-again. Am J Nurs 2016;116:22-23.

16. Pepe P, Aragona F. Morbidity after transperineal prostate biopsy in 3000 patients undergoing 12 vs 18 vs more than 24 needle cores. Urology 2013;81:1142-1146.

17. Ekwueme K, Simpson H, Zakhour H, et al. Transperineal template-guided saturation biopsy using a modified technique: outcome of 270 cases requiring repeat prostate biopsy. BJU Int 2013;111:E365-E373.

18. Hansen N, Patruno G, Wadhwa K, et al. Magnetic resonance and ultrasound image fusion supported transperineal prostate biopsy using the Ginsburg protocol: Technique, learning points, and biopsy results. Eur Urol 2016;70:332-340.

19. Bass EJ, Donaldson IA, Freeman A, et al. Magnetic resonance imaging targeted transperineal prostate biopsy: a local anaesthetic approach. Prostate Cancer Prostatic Dis 2017;20:311-317.

20. McGrath S, Christidis D, Clarebrough E, et al. Transperineal prostate biopsy - tips for analgesia. BJU Int 2017;120:164-167.

21. Iremashvili VV, Chepurov AK, Kobaladze KM, et al.

Periprostatic local anesthesia with pudendal block for transperineal ultrasound-guided prostate biopsy: a randomized trial. Urology 2010;75:1023-1027.

22. Smith JB, Popert R, Nuttall MC, et al. Transperineal sector prostate biopsies: a local anesthetic outpatient technique. Urology 2014;83:1344-1349.

23. Merrick GS, Irvin S, Fiano R, et al. Pathology and quality of life outcomes following office-based transperineal prostate biopsy. Urology 2016;94:24-28.

24. Dundee PE, Grummet JP, Murphy DG. Transperineal prostate biopsy: template-guided or freehand? BJU Int 2015;115:681-683.

25. Raaijmakers R, Kirkels WJ, Roobol MJ, et al. Complication rates and risk factors of 5802 transrectal ultrasound-guided sextant biopsies of the prostate within a population-based screening program.

Urology 2002;60:826-830.

26. Symons JL, Huo A, Yuen CL, et al. Outcomes of transperineal template-guided prostate biopsy in 409 patients. BJU Int 2013;112:585-593.

in Rochester, Minnesota, and Charat Thongprayoon, MD, of the Department of Internal Medicine at Bassett Medical Center in Cooperstown, New York.

The researchers noted that an association between ESRD and kidney cancer is well known, but the risk of urothelial cancers in ESRD patients is unclear.

Epidemiologic studies, they stated, have identified risk factors for kidney cancer and urothelial cancers, including genetic factors, obesity, cigarette smoking, and exposure to chemical carcinogens such as aristolochic acid.

In a discussion of study limitations, the authors acknowledged that because

their meta-analysis included only observational studies, it can only establish an association between ESRD and urologic cancers, not causation. They also pointed out that it is possible urologic cancers were detected and diagnosed due to more intensive routine cancer screening among ESRD patients. â&#x2013;

32 Renal & Urology News

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Practice Management Nurse managers are critical to the efficient functioning of a medical practice and the quality of care it provides BY TAMMY WORTH nurse leaders can control and which have the greatest influence on nursing outcomes. Patient outcomes were more influenced by appropriate staffing and teamwork.

Teamwork/communication Nurse managers have a direct impact on the quality of care provided by staff nurses, Ross said. They shape how each nurse feels, which affects burnout, turnover, and patient satisfaction.

Consequently, it is important to foster qualities such as teamwork, accountability and good communication.

“I truly believe the biggest thing you can do [as a nurse manager] is to be a great mentor and have skills as a good listener and good communicator,” Ross said. “A nurse manager has to be professional and supportive and speak up for staff, because they recognize it if you don’t. And you can’t just sit and delegate, but you have to get out there and get your hands dirty.”

One of the strategies identified in the Press Ganey report as a way to drive improvement is the unit huddle. “One nurse manager described creating a huddle board that nurses on all of the shifts contribute to on a daily basis to identify small issues before they become big ones,” the report stated. “All of the

The keys to effective management are good communication, interpersonal cooperation, and a focus on education.

“Nurse managers set the tone for how effective and efficient the employees and staff will be,” said Seun Ross, Director of Nursing Practice and Work Environment at the American Nurses Association. “Nurses represent the largest subgroup of health care professionals, and they provide the most care, which places them at a prime position to affect outcomes.”

According to researchers, autonomy and professional development are factors

nurses on the unit are encouraged to place idea cards with proposed solutions on the board as well.”

Autonomy Another term for autonomy is transformational leadership, which Di Leonardi describes as the “leader getting out of the way.” In fact, she thinks that the term manager in the nurse manager title may send the wrong message. Managers keep staff in line, but

© KUPICOO / GETTY IMAGES

B

ette Case Di Leonardi remembers a nurse manager she encountered at a major urban medical center early in her career. The head nurse ran the unit with such a tight hand she terrified everyone who worked for her.

“The staff were fearful and nearly trembling when they walked past her,” Di Leonardi said.

But her tough leadership style worked.

They were so afraid of their boss that they worked hard and the care provided in the unit was terrific, she said.

That management approach would not be well-received today, though. It would erode morale and make it difficult to retain nurses, said Di Leonardi, now a nursing professional development consultant based in Chicago. The concept of a healthy workplace now is the antithesis of what she experienced as a young nurse, but nurse managers still set the tone. The keys to effective management are good communication, interpersonal cooperation, and a focus on education.

A 2017 Press Ganey Nursing Special Report that examined nurse and patient experience surveys found that nurse leaders have a substantial influence on the quality of the work environment and on safety, quality, and patient outcomes. Effective leadership at the top can improve all of these areas.

Nurse managers have a direct impact on the quality of care provided by staff nurses.

leaders empower staff. “This encourages autonomy and the nurses to step up and function and think beyond the direct care they are providing that day,” she said.

All nurses can be asked to help with things such as practice improvement or rounding or better use of the white board. When managers fail to seek involvement from the staff, their solutions are rarely those that take into account the whole group.

Good leadership is oriented toward the future, Di Leonardi said. Instead of just ensuring there are enough supplies, a good leader looks at how those supplies impact patient outcomes.

Professional development Professional development can come in many forms, not just in continuing education hours. Because the patient care environment is driven largely by metrics, an important development opportunity is data tracking to help staff improve front-line work. There is no way to know, for instance, if a dialysis center is seeing the number of patients it should in a day or the number of line infections if no one tracks those data. Nurse managers are in the best position to do that, as staff nurses are focused on patient care. If data suggest that targets are not being met,

a good nurse manager would consult with staff nurses to understand why.

Nurse managers spend much of their time on staffing: They are always scrambling to staff the next shift.

“Even though some managers are good at staffing and proud of the fact that they can create and fill schedules, the staffing burden can suck a lot of the joy out of the job,” Di Leonardi said.

Leadership support Physicians can play a role in supporting the work of nurse managers in clinic or hospital setting. One of the most important, according to Ross, is to help cultivate interprofessional collaboration, which is the quickest path to quality care. “We have to remember we are all in the same business and recognize that collaboration is vital to nurse leaders’ role as they spend more time in the unit,” she said.

Everyone needs to be involved in patient care, including patients and their families. A physician leader and nurse leader should work as a team to convey the expectations and desired outcomes, Ross said. “They need to be having meaningful conversations with their staff instead of just pushing information out,” she said. n Tammy Worth is a freelance medical journalist based in Blue Springs, MO.