Renal & Urology News - March/April 2018

M A R C H /A P R I L 2 0 1 8

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V O L U M E 17, I S S U E N U M B E R 2

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www.renalandurologynews.com

PCa Drugs Decrease Metastasis Risk Apalutamide and enzalutamide prolong metastasis-free survival in men with non-metastatic CRPC IMPROVED METASTASIS-FREE SURVIVAL In separate studies of men with non-metastatic castration-resistant prostate cancer who continued to receive androgen-deprivation therapy (ADT), those treated with apalutamide or enzalutamide had longer metastasis-free survival than those who received placebo. Shown here are the median survival times in months.

50

MONTHS

40

40.5

36.6

30

16.2

20

14.7

10 0

Apalutamide

Placebo

Enzalutamide

Placebo

Sources: Smith MR, Saad F, Chowdhury S, et al. Apalutamide treatment and metastasis-free survival in prostate cancer. N Engl J Med. 2018; published online ahead of print. Hussain M, Fizazi K, Saad F, et al. PROSPER: A phase 3, randomized, double-blind, placebo (PBO)-controlled study of enzalultamide (ENZA) in men with nonmetastatic castration-resistant prostate cancer (M0 CRPC).

Data presented at the 2018 Genitourinary Cancers Symposium. Abstract 3.

CN Ups Survival Odds in mRCC SAN FRANCISCO—New study findings presented at the 2018 Genitourinary Cancers Symposium may help to clarify the role of cytoreductive nephrectomy (CN) in the treatment of metastatic renal cell carcinoma (mRCC).

Bimal Bhindi, MD, and colleagues at Mayo Clinic in Rochester, Minnesota,

showed that upfront CN may offer better survival in appropriate surgical candidates compared with first-line targeted treatment. In another study, Jeffrey Graham, MD, of Tom Baker Cancer Centre at the University of Calgary in Alberta, Canada, and colleagues found that CN for mRCC continued on page 30

POINTS TO CONSIDER IN LYMPHOCELE PREVENTION

Strategies may include creating a peritoneal advancement flap.

PAGE 15

BY JODY A. CHARNOW SAN FRANCISCO—Treatment of non-metastatic castration-resistant prostate cancer (CRPC) with apalutamide or enzalutamide, both orally administered androgen receptor inhibitors, prolongs metastasis-free survival (MFS), according to the findings of separate studies presented at the 2018 Genitourinary Cancers Symposium.

Apalutamide is a next-generation medication that received FDA approval on February 14 for use in men with non-metastatic CRPC. Enzalutamide received FDA approval for treating metastatic CRPC in August 2012, but is not yet approved for use in men with non-metastatic CRPC.

For Untreated mRCC, Combo May Be Better

BY JODY A. CHARNOW COMBINED TREATMENT with atezolizumab and bevacizumab for untreated metastatic renal cell carcinoma (mRCC) is associated with better progression-free survival (PFS) compared with sunitinib, according to study findings presented at the 2018 Genitourinary Cancers Symposium.

The benefit appears to be greater in patients with PD-L1 positive tumors.

The phase 3 study (IMmotion151), which began in 2015, enrolled 915 adult patients with mRCC who were randomly assigned to receive the immunotherapy atezolizumab plus the targeted therapy bevacizumab intravenously every 3 weeks or sunitinib, an orally administered drug, daily for 4 weeks, followed by 2 weeks off treatment.

Atezolizumab is an immune checkpoint inhibitor that blocks the PD-L1 protein on tumor cells, thereby allowing the immune system to recognize and attack those cells. Bevacizumab continued on page 30

In the phase 3, randomized, doubleblind, placebo-controlled SPARTAN trial, men with non-metastatic CRPC treated with apalutamide had a significant 72% lower risk of metastasis or death compared with placebo recipients, with a median 2-year improvement in MFS, said lead investigator Eric Jay Small, MD, Professor and Chief, Division of Hematology and Oncology, University of California, San Francisco (UCSF), and Deputy Director of the UCSF Helen Diller Family Comprehensive Cancer Center, who presented study findings at the symposium. In addition, the investigators observed a 55% risk reduction in time to symptomatic progression. The continued on page 30

IN THIS ISSUE 6

Testosterone therapy does not elevate cardiovascular risks

19

Statins tied to better survival in men with advanced PCa

19

Perioperative aspirin use need not contraindicate RP

21

Meropenem-vaborbactam found superior for complicated UTI

22

Aspirin may ease vasculogenic erectile dysfunction

28

Urgency urinary incontinence linked to prior stroke or TIA

31

Ultra-low contrast volume could reduce CIN risk

A single PSA screening test has no effect on prostate cancer death risk.

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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”

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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.

T:13.5”

S:12”

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.

T:13.5”

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2 Renal & Urology News

MARCH /APRIL 2018 www.renalandurologynews.com

Pulmonary Hypertension May Up Risks in CKD PULMONARY hypertension may increase the risks for cardiovascular events and death in patients with any degree of kidney disease, according to new study findings.

In a systematic review and metaanalysis of 16 studies including 7112 patients with chronic kidney disease

(CKD) or kidney failure, 23% had co-existing pulmonary hypertension diagnosed by Doppler echocardiography. The presence of pulmonary hypertension, compared with its absence, was associated with 1.4-, 2.3-, and 2.1-fold higher risks for all-cause mortality among patients with CKD,

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.

end-stage renal disease (ESRD) receiving dialysis, or a functioning kidney transplant, respectively, Mengyao Tang, MD, MPH, of Harvard T.H. Chan School of Public Health in Boston, and colleagues reported in the American Journal of Kidney Diseases.

The risks were similar for patients 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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receiving hemodialysis or peritoneal dialysis. The cutoff value used to diagnose pulmonary hypertension did not alter results.

Pulmonary hypertension also was associated with more than double the risk for cardiovascular mortality in patients with CKD or ESRD. n 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

Q2

www.renalandurologynews.com MARCH /APRIL 2018

Renal & Urology News 3

Preop CKD Predicts Radical Cystectomy Outcomes PATIENTS WITH advanced chronic kidney disease (CKD) are at increased risk for adverse outcomes following radical cystectomy (RC) for bladder cancer, according to a new study.

To evaluate the association between preoperative CKD and oncologic outcomes, Tohru Nakagawa, MD, PhD, 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)

of the University of Tokyo in Japan, and colleagues reviewed the medical records of 594 Japanese patients with urothelial carcinoma of the bladder (UCB, median age 67 years) who underwent RC from 1990 to 2013. Of these, 65.3% had G1 to G2, 20.5% G3a, 8.6% G3b, and 5.6% G4 to G5 p ­ reoperative CKD. 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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Because chemotherapy can cause acute kidney injury, patients who received prior neoadjuvant chemotherapy were excluded from the study.

During a median follow-up of 4 years, 200 patients experienced cancer progression and 164 died from UCB. The 5- and 10-year progression-free rates 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

were 64.9% and 62.3%, respectively, and the 5- and 10-year cancer-specific survival rates were 70.2% and 66.1%, respectively, according to findings published in the World Journal of Urology (2018;36:249-256).

On multivariate analyses, having CKD stage G3b or higher was significantly associated with worse progression-free and cancer-specific survival, along with advanced pT stage and lymph node involvement. Compared with patients who had G1–2 CKD, those with G3b and G4–5 CKD had a significant 1.6fold and 2.2-fold increased risk of progression, respectively, and 1.7-fold and 2.4-fold increased risk of cancer-specific mortality, respectively. Compared with patients who had pT stage 0–1, those with pT stage 2 and 3–4 had a significant 1.8-fold and 3.2-fold increased risk

Patients with higher CKD stages are at greater risk of death from bladder cancer. of progression, respectively, and 1.8fold and 3-fold increased risk of cancerspecific mortality (CSM), respectively.

Patients with positive lymph nodes had a 3-fold increased risk of progression and CSM. Lymphovascular invasion was associated with a 2-fold increased risk of progression and CSM. “To our knowledge, this is the first study which clearly showed that preoperative CKD stages G3b or greater were significantly associated with poor oncological outcomes in UCB patients who underwent RC,” Dr Nakagawa’s team stated.

The mechanisms underlying the association between CKD stage and oncologic outcomes among patients with UCB is unclear. It is possible that patients with advanced CKD stages might receive less intensive treatment, the authors noted. There also could be a direct link between tumor aggressiveness and CKD status. As the investigators explained, CKD is a state of chronic inflammation induced by continuous oxidative stress, which in turn can activate inflammatory pathways, leading to the transformation of normal cells into tumor cells, tumor proliferation, and angiogenesis. “Uremic toxins may further accentuate the mitogenesis and cell differentiation in malignant tumors, leading to the formation of more aggressive tumor,” they wrote. n

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FROM THE MEDICAL DIRECTOR EDITORIAL ADVISORY BOARD

Prostate Cancer Survival Metrics: A New Standard?

T

he debate over which clinical endpoints best measure the efficacy of a cancer intervention persists. Value is in the eye of the beholder. For patients with advanced malignancies, improving overall survival (OS) remains the “holy grail,” the gold standard in most randomized clinical trials. Either a drug statistically extends your life or it does not.

Critics justifiably have argued that OS is not the only important measure of the success of a pharmacologic intervention. Other primary and secondary endpoints include progression-free survival (PFS), disease-free survival (DFS), metastasisfree survival (MFS), overall response rates (ORR), complete durable responses, patient reported outcomes, and other surrogate (often biomarker) endpoints. Effective clinical trial design and ultimately drug approval require careful consideration of the endpoints selected, and, increasingly, a dialogue with investigators and regulatory agencies regarding their willingness to accept survival endpoints short of OS. In prostate cancer (PCa), this debate is particularly sharp, whereas the natural history of advanced PCa often extends for years. Therefore, a patient who progresses to castration-resistant disease may be exposed to multiple treatments over several years prior to his death. As novel, sequential and combination therapies improve longevity, measuring the effects on OS by a medication tested years earlier becomes incrementally problematic.

The FDA approval of apalutamide on February 14, 2018 (see article on page 11) for patients with non-metastatic castrate-resistant prostate cancer (nmCRPC) reflects the agency’s growing awareness that clinically meaningful cancer endpoints exist in PCa short of OS.1 Approval was based on the results of the SPARTAN trial (NCT01946204), which randomized 1,207 patients with nmCRPC (2:1) to receive either apalutamide, an oral non-steroidal antiandrogen, or placebo in combination with ADT. MFS (time from randomization to first evidence of distant metastasis or death) was 40.5 months for apalutamide vs 16.2 months for placebo (hazard ratio 0.28; 95% CI: 0.23, 0.35; p<0.0001).2 While OS data are not yet mature, there are tantalizing hints that MFS may be a good surrogate for OS. Moreover, living metastasis free for an additional 2+ years may not only decrease the risks of skeletal-related events such as pathologic fractures, but likely provides a measurable psychological boost to patients.

These debates bring us back to the concept of value in health care.

That requires a conversation between multiple stakeholders. It should be recognized that the FDA is increasingly listening.

Robert G. Uzzo, MD, FACS G. Willing “Wing” Pepper Chair in Cancer Research Professor and Chairman, Department of Surgery Fox Chase Cancer Center Temple University School of Medicine, Philadelphia 1. https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm596796.htm 2. Smith MR et al: NEJM Feb 8, 2018

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 Jody A. Charnow Web editor

Natasha Persaud

Production editor Kim Daigneau

Group art director, Haymarket Medical Jennifer Dvoretz

Production manager Krassi Varbanov

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

Kathleen Walsh Tulley

General manager, medical communications

Jim Burke, RPh

Lee Maniscalco

CEO, Haymarket Media Inc.

Renal & Urology News (ISSN 1550-9478) Volume 17, Number 2. 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.

Contents

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MARCH /APRIL 2018

MARCH/ APRIL 2018 ■ VOLUME 17, ISSUE NUMBER 2

Urology 6

ONLINE

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this month at renalandurologynews.com 19

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

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HIPAA Compliance

Cardiovascular Event Risk Lower with TRT Use In a study, the 2-year absolute risk of cardiovascular events was 8.2% for testosterone replacement therapy recipients compared with 10.5% among controls.

Factors Affecting PAE Outcomes Identified Initial prostate size and percentage reduction in prostate volume predict outcomes among men who undergo prostatic artery embolization.

Statins May Up PCa Patient Survival In a study of men with high-risk prostate cancer, post-diagnostic use of statins was associated with a 47% lower risk of PCa mortality compared with patients with no documented statin use.

Aspirin Found Effective for Erectile Dysfunction Aspirin 100 mg/day for 6 weeks improved vasculogenic erectile function, especially among with a high mean platelet volume.

Our latest column offers tips for ensuring security of patient portals..

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

Nephrology 11

Dialysis Pts Often Readmitted After CVD Hospitalization A study revealed a 30-day all-cause readmission rate of 34.2%.

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Elevated SUA Trajectories Raise ESRD Risk in CKD Compared with patients who had a low uric acid trajectory, those with a high trajectory had an approximately 2.8-fold greater risk of ESRD.

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Ultra-low Contrast Volume May Lower CIN Risk In a small study, researchers observed a renoprotective effect with a median contrast volume of 13 mL for diagnostic coronary angiography.

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CAC Risk Factors in Chronic Kidney Disease Identified Patients with higher coronary artery calcification scores tended to have elevated levels of 24-hour urine albumin, cystatin C, and serum phosphate.

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 American Urological Association 2018 annual meeting in San Francisco, May 18–21.

In terms of changing practice, I think that our

results are probably consistent with a growing awareness that the cardiovascular and thrombotic risks of TRT may be less than once feared in younger, relatively healthy men.

See our story on page 6

Renal & Urology News 5

CALENDAR American Urological Association Annual Meeting San Francisco, CA May 18–21 ERA-EDTA 55th Congress Copenhagen, Denmark May 24–27 American Transplant Congress Seattle June 2–6 Canadian Urological Association Annual Meeting Halifax, Nova Scotia June 23–26.

International Continence Society Annual Meeting Philadelphia August 28–31 American Society of Nephrology Kidney Week New Orleans October 23–28 Large Urology Group Practice Association (LUGPA) 2018 Annual Meeting Chicago November 2–3

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Departments 4

From the Medical Director Moving the needle on prostate cancer survival

11

News in Brief Nocturia in men linked to smoking

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Practice Management Strategies for avoiding physician burnout

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Cardiovascular Event Risk Lower with TRT Use

BY JODY A. CHARNOW MEN WHO take testosterone replacement therapy (TRT) are not more likely to experience cardiovascular events or thromboembolism, but they are at higher risk of obstructive sleep apnea (OSA), according to a new study.

In fact, the study of 6844 male US military service members, retirees, and their dependents found that TRT was associated with a small but significant decrease in cardiovascular (CV) event risk, mainly due to a lower incidence of coronary artery disease (CAD), Alexander P. Cole, MD, of Brigham and Women’s Hospital in Boston, and colleagues reported in a paper published online ahead of print in BJU International.

The 2-year absolute risk of cardiovascular events was 8.2% for TRT users compared with 10.5% among controls (men not using TRT and who had no history of prostate cancer, cardiovascular disease, thromboembolism, or OSA). When the investigators looked

The therapy may increase the risk of obstructive sleep apnea, study finds. at congestive heart failure, stroke, and CAD separately, CAD was the only endpoint with significantly lower risk among TRT users.

The 2-year absolute risk of thromboembolic events was 2% in the TRT group and 1.4% among controls, a nonsignificant difference between groups.

The 2-year absolute risk of OSA was significantly greater among TRT than controls (16.5% vs 12.7%). “While previously demonstrated in small prospective studies, this association has not previously been shown in a large national study such as this,” Dr Cole’s team noted.

Possible explanations for the association include morphologic and neuromuscular changes to the airways, changes in metabolic requirements, and changes to the physiologic response to hypoxemia and hypercapnia, the investigators noted.

For the study, Dr Cole and his colleagues relied on data extracted from the Military Health System Data Repository, which includes inpatient and outpatient coding and pharmacy information for patients covered by the TRICARE benefit.

The study population consisted of 3422 TRT users and 3422 controls matched by birth year, race, marital status, military rank, comorbid conditions, and residence region. Men in both groups had a median age of 51 years.

With regard to study limitations, the authors pointed out that their study

population, although geographically diverse, may differ from the civilian population, thus limiting the generalizability of their findings. Another limitation may be the possibility of unmeasured confounders. These include patient characteristics not captured by diagnostic codes, such as the

specific ­etiology of low testosterone levels. In addition, they explained that because the data source consisted of International Classification of Diseases diagnostic and procedure codes obtained from the TRICARE insurance program, they lacked ­granular information on how OSA was diagnosed. They

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also were unable to analyze TRT doses.

“This latter point is certainly a limitation, given some evidence for a dosedependent effect of TRT.” In the past few years, TRT use has increased dramatically in relatively healthy men without definitive testicular or pituitary disease, but with testosterone levels below reference ranges for young men, Dr Cole told Renal & Urology News. “This has led to a lot of

controversy, especially given that many of the symptoms of hypogonadism such as fatigue, decreased libido, and adiposity are sometimes considered part of the ‘natural’ aging process, and also given some recent high-profile studies suggesting associations between testosterone replacement and medical side effects like heart disease.”

A problem with some of these studies, Dr Cole noted, is that they were

disproportionately in older men, in some instances individuals with mobility impairments and other health problems.

“In terms of changing practice, I think that our results are probably consistent with a growing awareness that the cardiovascular and thrombotic risks of TRT may be less than once feared in younger, relatively healthy men,” Dr Cole said. “Regarding the modest

Renal & Urology News 7

increase in sleep apnea, this is important. The Endocrine Society Guidelines do include pre-existing OSA as a relative contraindication for TRT. Given our findings, I think that this may be an increasingly important topic for men considering TRT.” A collaboration between the Center for Surgery and Public Health at Brigham and Women’s Hospital and continued on page 8

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the Uniformed Services University of the Health Sciences in Bethesda, Maryland, the study was funded by the Henry M. Jackson Foundation for the Advancement of Military Medicine.

A study published last year in JAMA Internal Medicine (2017;177:491-499) also found a lower risk of CV events among TRT users. In a retrospective analysis of 44,335 men aged 40 years and older (8808 who had ever been

dispensed TRT and 35,527 never dispensed TRT), T. Craig Cheetham, PharmD, MS, of the Southern California Permanente Medical Group in Pasadena, and colleagues found that TRT recipients had a significant 33% lower risk of a composite of acute myocardial infarction (AMI), coronary revascularization, unstable angina, stroke, transient ischemic attack (TIA), and sudden cardiac

death (SCD) ­compared with men who never received TRT. The investigators found similar results when looking separately at combined cardiac events (AMI, SCD, unstable angina, coronary revascularization) and combined stroke events (stroke and TIA). The TRT group had a significant 34% and 28% lower risk of cardiac events and stroke events compared with the noTRT group, respectively.

A study of 76,639 US veterans published last year in the Journal of the American Heart Association by Rishi Sharma, MD, of the Kansas City VA Medical Center in Kansas City, Missouri, and colleagues found that normalization of testosterone levels following TRT was associated with a significant 21% decreased risk of atrial fibrillation compared with men who did not receive TRT. n

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Higher-Dose IV Iron Appears Safe in Dialysis Patients HIGHER DOSES of intravenous (IV) iron do not appear to be associated with a greater risk of mortality and other adverse outcomes, according to a new review and meta-analysis published online ahead of print in the Clinical Journal of American Society of Nephrology.

Navdeep Tangri, MD, PhD, of the University of Manitoba in Winnipeg, Canada, and collaborators analyzed data from 7 randomized controlled trials (RCTs) and 15 observational studies including more than 140,000 participants published on or before January 2017. The higher-dose IV iron

group exceeded 200 and 400 mg per month in most of the observational studies and RCTs, respectively, and the lower-dose IV iron group fell below 200 mg per month. The investigators observed no greater risks of mortality, infections, cardiovascular events, or hospitalizations among higher-dose

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IV iron r­ ecipients compared with the lower-dose group in either the RCTs or observational studies.

In a discussion of study limitations, the investigators noted that only 3 studies included patients on peritoneal dialysis, a population in which IV iron is used less frequently. n

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MRI May Help Avoid Unnecessary Prostate Biopsies ADDING multiparametric magnetic resonance imaging (MRI) findings to conventional clinical predictors in a prostate cancer risk stratification model increases diagnostic accuracy and may reduce the number of unnecessary biopsies while maintaining a high rate of diagnosis of clinically

s­ ignificant prostate tumors, according to a new study.

In a validation cohort, the area under the curve (AUC) increased from 64% with a baseline model to 84% with a model that incorporated multiparametric MRI-derived prostate volume and PI-RADSv2 category as well as

the clinical predictors in the baseline model (age, race, prior biopsy findings, results of a digital rectal examination [DRE] and PSA level).

At a risk threshold of 20%, the MRIbased model had a lower false-positive rate than the baseline model (46% vs 92%), with only a small reduction in

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the true-positive rate (89% vs 99%), a team led by by Baris Turkbey, MD, of the National Cancer Institute (NCI) in Bethesda, Maryland, reported online ahead of print in JAMA Oncology. At a 20% risk cutoff, 38% of biopsies could have been avoided with the MRI model compared with 6% of biopsies avoided by the baseline model.

“The net reduction in the number of false-positives based on the MRI model, compared with having to perform a biopsy in all patients with positive MRI results, was equivalent to performing 18 fewer unnecessary biopsies per 100 men, with no increase in the number of clinically significant prostate cancer left undiagnosed,” the investigators stated.

Adding MRI findings to conventional predictors improves diagnostic accuracy.

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Dr Turkbey and his colleagues created the MRI-based model based on the findings from a development cohort of 400 patients enrolled at NCI and a validation cohort of 251 patients enrolled at the University of Chicago Medical Center and the University of Alabama at Birmingham. All participants underwent MRI, MRI-transrectal ultrasound (MRI-TRUS)-guided prostate biopsy, and 12-core systematic biopsy.

The development cohort included patients with elevated PSA levels or abnormal findings on a digital rectal examination and at least 1 lesion detected on multiparametric MRI scans. All detected lesions were evaluated and assigned a category based on the PI-RADSv2 guideline. Patients with category 3 or higher lesions routinely underwent MRI-TRUS fusion-guided biopsy, whereas those with category 1 or 2 lesions were targeted only under certain circumstance or based on patient preference. Only the category of the index lesion was considered in this study and was defined by gthe highest PI-RADSv2 category in the prostate.

For the validation cohort, investigators used the same enrollment criteria as used for the development cohort. All patients underwent multiparametric MRI, and lesions were assigned PI-RADSv2 categories. Investigators also applied the same definitions for index lesions and biopsy decision rules. n

www.renalandurologynews.com MARCH /APRIL 2018

Renal & Urology News 11

News in Brief

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

Short Takes Factors Affecting PAE Outcomes Identified

and colleagues at Mayo Clinic in

INITIAL PROSTATE SIZE and percentage

172 (66%) received palliative care

reduction in prostate volume predict

consultation within 6 months of

outcomes among men who undergo

death; 61 (36%) of these patients’

prostatic artery embolization (PAE) for

initial consultations occurred in the

benign prostatic obstruction, research-

inpatient setting. On multivariable

ers reported online in C ­ ardiovascular

analysis, longer duration of HD and

and Interventional Radiation.

recent hospitalization prior to death

Rochester, Minnesota, found that

The findings are from a prospec-

were significantly associated with

tive follow-up study of 86 men who

palliative care consultation within

underwent PAE, of whom 62 (72.1%)

6 months of death.

had achieved clinical success at 12 MBChB, and colleagues at University

Expanded Indications Approved for UroLift

Hospital Southampton in Southamp-

FDA HAS APPROVED new indications

ton, UK, found that percentage

for the UroLift System (NeoTract),

volume reduction at 3 months had the

a treatment for benign prostatic

strongest correlation with good symp-

hyperplasia that involves placement,

tomatic outcome at 12 months.

via a minimally invasive procedure, of

months. Investigators Drew Maclean,

permanent implants that relieve pros-

Palliative Care Common With HD Discontinuation

tatic obstruction and open the urethra.

MOST PATIENTS who discontinue

men with an obstructive median lobe

hemodialysis (HD) prior to death

and men as young as 45 years. Previ-

do so with the aid of palliative care

ously, UroLift was contraindicated in

teams, researchers reported at the

patients with an obstructive median

2018 Annual Dialysis Conference in

lobe and only approved for men aged

Orlando, Florida.

50 years and older. FDA granted the

UroLift is now approved for use in

In a study of 262 adult patients who discontinued HD, Joy C.Y. Chen, MD,

expanded indications based on the results of the MedLift study.

Urologic Surgeries Compared A study of major urologic surgeries found that radical cystectomy (RC) is associated with higher 90-day rates of complications and hospital readmission than radical nephrectomy (RN) or radical prostatectomy (RP).

27% 70 n 90-day complication rate 60 n 90-day readmission rate 50

39%

40 30

19.9%

20 10 0

14.2%

5.9%

1.9% RP

RN

RC

Source: Mossanen M, Krasnow RE, Zlatev DV, et al. Incidence and predictors of mortality following major urologic cancer surgery. Data presented in poster format at the 2018 Genitourinary Cancers Symposium, held in San Francisco Feb. 8–10. Abstract 435.

FDA Approves Apalutamide for Non-metastatic CRPC F

or the first time, the FDA has approved a medication for the treatment of nonmetastatic castration-resistant prostate cancer (CRPC), according to a press release from the agency. The drug, apalutamide, is an orally administered androgen receptor inhibitor. The drug, which was approved on February 14, will be marketed as Erleada by its developer, Janssen Pharmaceutical Companies.

According to the FDA, the approval is the first to use the end point of metastasis-free survival (MFS). The agency based its approved on safe and efficacy data from a phase III randomized, double-blind clinical trial (SPARTAN) that included 1207 patients with non-metastatic CPRC. In that trial, the median MFS was 40.5 months for men taking apalutamide compared with 16.2 months for those receiving a placebo. Apalutamide-treated patients had a significant 72% decreased risk of metastasis or death compared with placebo recipients.

Metabolic Syndrome, Smoking May Up Nocturia Risk in Men M

etabolic syndrome (MetS) and smoking are independently associated with an increased risk of moderate or severe nocturia in men with lower urinary tract symptoms (LUTS) and benign prostatic hyperplasia (BPH), investigators reported online ahead of print in Prostate Cancer and Prostatic Diseases.

Cosimo De Nunzio, MD, and collaborators at “La Sapienza” University of Rome in Italy, enrolled 492 patients with BPH/LUTS. The men had a median age of 68 years and median body mass index of 26.5 kg/m2. Of these men, 212 (43.1%) reported moderate or severe nocturia. MetS was diagnosed in 147 (29.9%) patients, and of them, 89 (60.5%) complained of moderate or severe nocturia.

In addition, 187 patients (38%) were current smokers. Of them, 99 (52%) presented with moderate or severe nocturia. On multivariate analysis, MetS and smoking were associated with a significant 2.5-fold and 1.7-fold increased odds of moderate or severe nocturia, respectively.

Dialysis Pts Often Readmitted After CVD Hospitalization M

ore than one third of dialysis patients hospitalized for cardiovascular disease (CVD) are readmitted to a hospital within 30 days, and less than half of these readmissions are related to CVD, according to study findings presented at the 2018 Annual Dialysis Conference in Orlando, Florida.

David T. Gilberston, PhD, and James Wetmore, MD, of the Chronic Disease Research Group, Minneapolis Medical Research Foundation, Minneapolis, Minnesota, analyzed data from 142,210 CVD-related hospitalizations of Medicareeligible dialysis patients from 2012 to 2013. The 10- and 30-day all-cause readmission rates were 15.6% and 34.2%, respectively. The CVD-related 10- and 30-day readmission rates were 6.6% and 14.7%, respectively. In addition, findings showed that 1.5% and 4.5% of patients died within 10 and 30 days following hospitalization.

“These findings demonstrate the high morbidity and mortality associated with CVD events in patients receiving dialysis,” the investigators concluded in their study abstract.

www.renalandurologynews.com MARCH /APRIL 2018

Renal & Urology News 15

n FEATURE

Lymphoceles: A Review and An Approach for Prevention Strategies may include creating a peritoneal advancement flap

BY DAVID CANES, MD, AND ALIREZA MOINZADEH, MD

David Canes, MD

capsule. It was first described using the term “lymphocyst” after a series of hysterectomies for cervical cancer by Mori in 19552. No official categorization system or severity grading system exists for post-surgical lymphoceles, but some people describe them by denoting how the diagnosis was made, either prompted by symptom-driven investigation (clinical) or incidental on abdominopelvic radiographic exam (radiographic/subclinical).

Pathophysiology, natural history

Alireza Moinzadeh, MD

M

ost prostatectomies are now being done with concomitant lymphadenectomy. A few factors are responsible. First, urologists are increasingly comfortable offering active surveillance for very-low-risk and most low-risk prostate cancers, all but removing them from the surgical realm. In a National Cancer Database study, 70% of prostatectomies were accompanied by pelvic lymph node dissection (PLND) in 2010– 2011,1 and we suspect this number has only risen since. Second, mounting data indicate that staging is improved with extended PLND (ePLND). It stands to reason that we now have renewed interest in assessing why lymphoceles seem to be an almost inevitable consequence of lymph node removal, uncovering the putative risk factors, and determining how they can be prevented.

A lymphocele, in basic terms, is a cystic cavity containing lymphatic fluid, with a fibrous (not epithelial lined)

The exact mechanism of lymphocele formation after either transperitoneal or extraperitoneal prostatectomy with lymphadenectomy is largely speculative.

Unsealed lymph channels allow for ongoing lymphorrhea that accumulates into a surgical space. Some collections ultimately resorb spontaneously. Peritoneum allows free absorption of lymph, so for persistent lymphoceles, the fluid cavity must be excluded or walled-off from the peritoneal cavity. In an extraperitoneal approach, exclusion from the peritoneum is easy to conceive, but is perhaps less obvious following a transperitoneal approach. Pelvic lymphoceles are rare following radical cystectomy with lymphadenectomy. This suggests the bladder plays a key role in walling off lymphocele cavities following prostatectomy. Indeed, the bladder usually forms the medial wall of a pelvic lymphocele cavity (Figure 1).

The incidence of lymphoceles naturally depends on the rigor with which one searches for them. Since followup does not routinely include imaging, the true incidence is unknown.3 If routine imaging is done, radiographic lymphoceles are quite common. Two studies have included routine CT scans

­ ostoperatively, one by Orvieto et al, in p which 51% had radiographic and 15.4% had clinical lymphoceles,4 and another

by Solberg et al, which found a 54% incidence of radiographic lymphoceles.5 If lymphoceles become symptomatic they typically do so at approximately the third postoperative week.6 Symptoms are predominantly related to local compression. The patient may report generalized abdominal or pelvic pain and pressure.

If the external iliac vein is compressed, leg edema or venous thrombosis may ensue. If the bladder is compressed, irritative urinary frequency occurs as the bladder is prevented from filling.

Similarly, constipation can occur from rectal compression. When secondarily infected, fever, chills, and even night sweats are seen. When symptomatic, most patients will require intervention either with percutaneous drain placement or laparoscopic marsupialization.7

Risk factors Standard vs extended lymphadenectomy.

The impact of lymphadenectomy extent has been studied. Interestingly, even when lymphadenectomy is omitted, the lymphocele rate is not zero,8 perhaps because even by mobilizing the bladder and defatting the anterior surface of prostate, lymphatic channels may be disrupted, though this is pure speculation. A standard PLND (sPLND) includes nodes bounded by the common iliac artery superiorly, external iliac vein laterally, node of Cloquet inferiorly, and the obturator nerve posteriorly.9 An ePLND extends the lateral border to the genitofemoral nerve, medially to the bladder wall and ureter, and includes the internal iliac nodes, including tissue below the obturator nerve.9 One might expect that the more lymphatic channels

transgressed over a larger lymphadenectomy template, the greater the likelihood of lymphocele formation. This remains controversial, however.

Naselli et al evaluated 359 patients undergoing PLND (98 sPLND, 249 ePLND) with a 12.6% lymphocele rate, 7.4% of which were symptomatic.9 On multivariate analysis, the number of nodes showed a significant linear association with symptomatic lymphocele formation.

Lymphoceles developed in 2% of the sPLND group compared with 9.6% of the ePLND group. Similarly, Briganti et al found a higher incidence of lymphocele in ePLND (10.3%) vs sPLND (4.6%) in a series of 963 patients.10 Other groups have found no difference in lymphocele rates by lympadenectomy extent. In a study of 492 robotic prostatectomies, Liss et al found similar (~5%) rates of lymphocele for both templates; however, in this series lymph node yield was statistically similar in the sPLND and ePLND groups.11 Yuh et al compared obturator nodes only to ePLND in 406 patients, and symptomatic lymphocele rates were very similar (2.2% and 2.5%).12 Heparin. Since lymphatic fluid contains similar coagulation factors as plasma,3 it has been postulated that anticoagulation may prolong lymphorrhea by keeping lymphatic channels open longer, though this remains controversial. In a fairly small Swedish study in 1994, 24 patients with and without heparin were compared for degree of lymph fluid buildup postop. The lymph fluid buildup was markedly higher in the heparinized group.13 In a similar study in 1992, Biggs and Catalona looked at 68 patients. In the group receiving prophylactic heparin, prolonged suction drainage for high drain output was more common.14 Continues on page 16

16 Renal & Urology News

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Others have found no association of lymphoceles with prophylactic heparin. In a study of 579 men undergoing prostatectomy with and without heparin, Sieber et al found no difference in lymphocele rates.15 In a study of almost 1500 patients, lymphocele rates were also no different whether or not heparin prophylaxis was administered.16 Lymph node positivity. Whether node status at the time of prostatectomy influences the likelihood of lymphocele development is another arena in which the literature is split. The issue may be difficult to untangle from extent of lymphadenectomy, since patients at highest risk of lymph node positivity typically receive a more thorough dissection, which is more likely to reveal positive nodes. In the Orvieto Study,4 on multivariate analysis, nodal involvement was associated with twice the risk of lymphocele formation (p=0.03). Other studies have not supported this observation. In a study by Capitanio et al of 552 prostatectomies, only age and number of nodes, and not lymph node status, predicted lymphocele.17 Patient age. As mentioned above, Capitanio et al found an increased clinically significant lymphocele risk of 5% for every year of age.17 However, in the study by Orvieto and colleagues, patient age was not a factor on univariate or multivariate analysis.4 Trans vs extraperitoneal prostatectomy.

One intuitively expects the lymphocele rate to be lower with a transperitoneal approach, but the lymphadenectomy cavity can still become walled off, typically by the bladder, as described earlier. Retrospective propensity matched analysis such as one by Horovitz and colleagues18 examined 3183 RARPs by a single surgeon, with 671 in each group.

Symptomatic lymphocele rates between the group were statistically similar: 2.83% after extraperitoneal and 1.49% after transperitoneal. Low event rates may hamper definitive conclusions.

Potential preventative strategies Investigators have explored various strategies to prevent lymphoceles from forming. Leaving a JP drain in longer to divert excess lymphorrhea rather than letting it accumulate makes intuitive sense.

Like many factors in this arena, results have been conflicting. In a randomized study, Danuser demonstrated the lowest rate of symptomatic lymphoceles among patient in whom a JP was left in for 7 days compared with 1 day or no drain at all.19 However, in this study, the overall lymphocele rate was similar in all groups.

In a study of 4173 prostatectomies with

David Canes, MD, and Alireza Moinzadeh, MD, are affiliated with the Lahey Institute of Urology at Lahey Hospital & Medical Center in Burlington, MA. REFERENCES

FIGURE 1: Right pelvic lymphocele, whereby the bladder forms the medial wall of the lymphocele cavity

bilateral ­pelvic lymph node dissection, Gotto et al found no association with the number of pelvic drains (1 or 2) and development of symptomatic lymphocele, or laterality of the lymphocele when laterality of drain placement was known.20 It seems likely that pelvic drainage adds little value to prevent lymphocele formation, probably because the duration of drainage would have to be quite longer than the ranges studied, as lymphoceles present on average 3 weeks postop.21 One might expect that rigorous clip application during lymphadenectomy would decrease the incidence of lymphoceles. A prospective randomized trial comparing titanium clip application to bipolar cautery found no difference in overall or symptomatic lymphoceles between groups.22 In an accompanying editorial, the observation that clips were only applied at the femoral canal was cited as a major study limitation.23 They argued that clips should either be applied liberally in all locations or not at all. As such, systematic use of extensive clipping can achieve a near zero lymphocele rate as reported by others.24 For those favoring an extraperitoneal approach to prostatectomy, making a large fenestration in the peritoneum at the end of a case may reduce the incidence of lymphocele formation.

Stolzenburg et al compared 50 patients with and without this technique and found a 32% lymphocele rate in patients without a fenestration compared with a 6% rate with fenestration.25 Why this linear fenestration does not rapidly seal over shortly postoperatively is difficult to conceptualize.

Virtually all types of hemostatic agents have been used in attempts to prevent lymphocele formation. In a study by Waldert et al, 32 patients had Floseal applied to the lymphadenectomy bed and 110 patients did not.26 The incidence of symptomatic lymphoceles decreased from 14.5% to 3.1% in favor of FloSeal®. Similarly lower lymphocele incidence has been found after TachoSil®

application.27 Authors generally hypothesize that a fibrin clot may be formed, reducing lymphorrhea. We hypothesize some sort of local sclerosant effect, akin to sclerosing of the pleural cavity or hydrocele sac whereby a hemostatic agent inflames and subsequently obliterates the potential cystic cavity, thus preventing lymphocele formation.

Peritoneal advancement flap: The Lahey Lymphocele Stitch Our institutional experience with lymphocele prevention began in 2012, when we began creating a peritoneal interposition flap using the visceral peritoneum of the bladder. Based on our observations that the bladder forms the medial wall of a pelvic lymphocele, and noting the scarcity of lymphoceles after cystectomy, the crucial role of the bladder in walling off a lymphocele was apparent. After transperitoneal robotic prostatectomy and pelvic lymphadenectomy, the available peritoneum folded around laterally and sutured to the bladder itself so that the bladder’s lateral aspect is now covered with visceral peritoneum. This prevents the bladder from adhering to and walling off the pelvic lymphadenectomy bed, allowing continuous egress of lymphatic fluid into the peritoneal cavity. Another way to conceive of this is creation of a fenestration up front at the time of prostatectomy, notwithstanding that the approach is already transperitoneal. In a nonrandomized study of 78 patients with a flap and 77 patients without a flap, there were no lymphoceles in the peritoneal advancement flap group compared with an 11.6% baseline lymphocele rate.28 This strategic suture fixation of available peritoneum bilaterally can be accomplished in less than 5 minutes at the end of the case. A multi-institutional randomized trial using the Lahey lymphocele stitch is in preparation. n For a video of the technique, please visit http://bit.ly/laheystitch

1. Wang EH, Yu JB, Gross CP, et al. Variation in pelvic lymph node dissection among patients undergoing radical prostatectomy by hospital characteristics and surgical approach: results from the National Cancer Database. J Urol. 2015;193:820-825.

2. Mori N. Clinical and experimental studies on the so-called lymphocyst which develops after radical hysterectomy in cancer of the uterine cervix. J Jpn Obstet Gynecol Soc. 1955;2:178-203.

3. Lee HJ, Kane CJ. How to minimize lymphoceles and treat clinically symptomatic lymphoceles after radical prostatectomy. Curr Urol Rep. 2014;15:445.

4. Orvieto MA, Coelho RF, Chauhan S, et al. Incidence of lymphoceles after robot-assisted pelvic lymph node dissection. BJU Int. 2011;108:1185-1190.

5. Solberg A, Angelsen A, Bergan U, et al. Frequency of lymphoceles after open and laparoscopic pelvic lymph node dissection in patients with prostate cancer. Scand J Urol Nephrol. 2003;37:218-221.

6. Gotto GT, Yunis LH, Guillonneau B, et al. Predictors of symptomatic lymphocele after radical prostatectomy and bilateral pelvic lymph node dissection. Int J Urol. 2011;18:291-296.

7. Fallick ML, Long JP. Laparoscopic marsupialization of lymphocele after laparoscopic lymph node dissection. J Endourol. 1996;10:533-534.

8. Khoder WY, Trottmann M, Buchner A, et al. Risk factors for pelvic lymphoceles post-radical prostatectomy. Int J Urol. 2011;18:638-643.

9. Naselli A, Andreatta R, Introini C, et al. Predictors of symptomatic lymphocele after lymph node excision and radical prostatectomy. Urology. 2010;75:630-635.

10. Briganti A, Chun FK, Salonia A, et al. Complications and other surgical outcomes associated with extended pelvic lymphadenectomy in men with localized prostate cancer. Eur Urol. 2006;50:1006-1013.

11. Liss MA, Palazzi K, Stroup SP, et al. Outcomes and complications of pelvic lymph node dissection during robotic-assisted radical prostatectomy. World J Urol.

2013;31:481-488.

12. Yuh BE, Ruel NH, Mejia R, et al. Standardized comparison of robot-assisted limited and extended pelvic lymphadenectomy for prostate cancer. BJU Int. 2013;112:81-88.

13. Tomic R, Granfors T, Sjödin JG, Ohberg L. Lymph leakage after staging pelvic lymphadenectomy for prostatic carcinoma with and without heparin prophylaxis. Scand J Urol Nephrol. 1994;28:273-275.

14. Bigg SW, Catalona WJ. Prophylactic mini-dose heparin in patients undergoing radical retropubic prostatectomy. A prospective trial. Urology. 1992;39:309-313.

15. Sieber PR, Rommel FM, Agusta VE, et al. Is heparin contraindicated in pelvic lymphadenectomy and radical prostatectomy? J Urol. 1997;158(3 Pt 1):869-871.

16. Chalmers DJ, Scarpato KR, Staff I, et al. Does heparin prophylaxis reduce the risk of venous thromboembolism in patients undergoing robot-assisted prostatectomy? J Endourol. 2013;27:800-803.

17. Capitanio U, Pellucchi F, Gallina A, et al. How can we predict lymphorrhoea and clinically significant lymphocoeles after radical prostatectomy and pelvic lymphadenectomy? Clinical implications. BJU Int. 2011;107:1095-1101.

18. Horovitz D, Lu X, Feng C, et al. Rate of symptomatic lymphocele formation after extraperitoneal vs transperitoneal robot-assisted radical prostatectomy and bilateral pelvic lymphadenectomy. J Endourol.

2017;31:1037-1043.

19. Danuser H, Di Pierro GB, Stucki P, Mattei A. Extended pelvic lymphadenectomy and various radical prostatectomy techniques: is pelvic drainage necessary? BJU Int. 2013;111:963-969.

20. Gotto GT, Yunis LH, Guillonneau B, et al. Predictors of symptomatic lymphocele after radical prostatectomy and bilateral pelvic lymph node dissection. Int J Urol. 2011;18:291-296.

21. Canes D, Cohen MS, Tuerk IA. Laparoscopic radical prostatectomy: omitting a pelvic drain. Int Braz J Urol. 2008;34:151-158.

22. Grande P, Di Pierro GB, Mordasini L, et al. Prospective randomized trial comparing titanium clips to bipolar coagulation in sealing lymphatic vessels during pelvic lymph node dissection at the time of robot-assisted radical prostatectomy. Eur Urol. 2017;71:155-158 23. Stolzenburg JU, Kyriazis I, Liatsikos E. Postoperative lymphocele formation after pelvic lymph node dissection at the time of radical prostatectomy should not be considered an inevitable consequence of the approach. Eur Urol. 2017;71:159-160.

24. Davis JW, Shah JB, Achim M. Robot-assisted extended pelvic lymph node dissection (PLND) at the time of radical prostatectomy (RP): a video-based illustration of technique, results, and unmet patient selection needs. BJU Int. 2011;108(6 Pt 2):993-998.

25. Stolzenburg JU, Wasserscheid J, Rabenalt R, et al.

Reduction in incidence of lymphocele following extraperitoneal radical prostatectomy and pelvic lymph node dissection by bilateral peritoneal fenestration.

World J Urol. 2008;26:581-586.

26. Waldert M, Remzi M, Klatte T, Klingler HC. FloSeal reduces the incidence of lymphoceles after lymphadenectomies in laparoscopic and robot-assisted extraperitoneal radical prostatectomy. J Endourol.

2011;25:969-973.

27. Simonato A, Varca V, Esposito M, et al. The use of a surgical patch in the prevention of lymphoceles after extraperitoneal pelvic lymphadenectomy for prostate cancer: a randomized prospective pilot study. J Urol.

2009;182:2285-2290.

28. Lebeis C, Canes D, Sorcini A, Moinzadeh A. Novel technique prevents lymphoceles after transperitoneal robotic-assisted pelvic lymph node dissection: Peritoneal flap interposition. Urology. 2015;85:1505-1509.

www.renalandurologynews.com MARCH /APRIL 2018

■ GUCS 2018, San Francisco

Renal & Urology News 19

2018 Genitourinary Cancers Symposium, San Francisco

Statins May Up PCa Patient Survival Studies reveal a lower death risk among statin users with advanced prostate cancer MEN WITH advanced prostate cancer (PCa) who take statins may experience a survival benefit, new studies suggest.

In a population-based study of 12,700 men with high-risk PCa identified using the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database, Grace L. Lu-Yao, PhD, of the Sidney Kimmel Cancer Center at Jefferson Medical College and the Jefferson College of Population Health in Philadelphia, and colleagues found that post-diagnostic use of statins was associated with a 47% lower risk of PCa mortality compared with patients with no documented statin use. Among obese patients, statin use was associated with a 62% decreased risk of PCa mortality.

The investigators observed a synergistic effect of statins and metformin among patients with metastatic disease.

Statin use alone by these patients was associated with a 22% decreased risk of PCa mortality, whereas concomitant use of a statin and metformin was

Overall PCa Detection Rate Drops FOLLOWING RELEASE of the 2012 US Preventive Services Task Force recommendations for prostate cancer (PCa) screening, the rates of PSA testing and overall PCa detection declined while the rate of patients presenting with metastatic PCa increased.

Joseph Presti, Jr., MD, and col-

a­ ssociated with a 46% decreased risk.

Notably, the study found that different statins varied in their effect, with atorvastatin appearing to offer the strongest protection. Atorvastatin users had an 82% decreased risk of PCa mortality compared with individuals who did not use statins. By comparison, use of lovastatin, pravastatin, rosuvastatin, and simvastatin was associated with a 55%, 18%, 67%, and 24% decreased risk, respectively.

This is the first human study to examine the effect of a combination of metformin and statin on PCa mortality risk, Dr Lu-Yao said.

In a separate study, Guillermo de Velasco, MD, PhD, of the Hospital 12 de Octubre in Madrid, Spain, and colleagues conducted a post-hoc analysis of data from the randomized clinical trials COU-AA-301 and COU-AA-302, in which men with mCRPC were treated with prednisone plus placebo or abiraterone. Results showed that statin

users had significantly better overall survival than non-users.

The reference group for both studies included patients in the placebo arm who did not use statins. Among statin users in the COU-AA-301 study, patients

Protective effect of statins was most pronounced for atorvastatin. treated with prednisone plus abiraterone had a significant 35% decreased risk of death compared with the reference group. The investigators observed no significant decrease in death risk among statin users in the placebo arm.

In the COU-AA-302 study, statin users in the abiraterone and placebo groups had a significant 33% and 29% decreased risk of death, respectively,

compared with the reference group.

In a third study, Jacob A. Gordon, MD, of the Vancouver Prostate Centre, University of British Columbia, Vancouver, Canada, and colleagues examined the effect of statin use on outcomes among patients with mCRPC receiving abiraterone, an anti-androgen that inhibits CYP17A1. Their analysis included 301 patients. Of these, 84 (28%) were statin users. The median overall survival for statin users and nonusers was 16.2 and 11.3 months, respectively. On multivariate analysis, statin use was associated with a borderline significant 21% decreased risk of death.

“Although limited by sample size, our data showed a trend that statins may mildly enhance the anti-tumor effects of [abiraterone] in CRPC patients,” the authors concluded.

The findings suggest that depletion of de novo cholesterol production may further limit androgen synthesis in concert with CYP17A1 inhibition. n

Early ADT Salvage Lowers PCSM Risk AMONG MEN who experience biochemical recurrence of prostate cancer following radiation therapy, early vs delayed initiation of salvage androgendeprivation therapy (ADT) for those with a long PSA doubling time may decrease the risk of prostate cancerspecific mortality (PCSM), new study findings suggest.

The findings challenge an unproven assumption that patients with a short PSA doubling time (PSADT) are those most likely to benefit from early initiation of salvage ADT, the investigators noted.

Out of a cohort of 206 men with localized unfavorable-risk prostate cancer randomized to radiation therapy (RT) or RT plus 6 months of ADT from 1995 to 2001, Brandon A. Mahal, MD, of Harvard Medical School in Boston, and colleagues selected 54 men who received salvage ADT for PSA failure after a median follow-up almost 18.72 years.

After a median follow-up of 5.68 years following salvage ADT, 49 men (91%) died, 27 from PCa, the investigators reported. Each 1-month increase

in PSADT was associated with significant 67% decreased risk of PCSM. Among patients with a long PSADT (6 months or more) initiating salvage ADT later (at a PSA level greater than 12 ng/mL) vs earlier was associated with a significant 8.8-fold increased risk of PCSM in adjusted analyses, according to Dr Mahal’s team. Later initiation of salvage ADT in men with a short PSADT (less than 6 months) was not significantly associated with an increased PCSM risk compared with earlier initiation. n

leagues from Kaiser Permanente Northern California (KPNC) in Oakland found that the PSA testing rate among screen-eligible men at KPNC declined from 42.7% during 2010– 2011 to 32.5% during 2014–2015.

Between these time periods, the relative rate of overall PCa detection decreased by 54.5% and the relative rate of metastatic PCa at presentation increased by 29%. n

Perioperative Aspirin Use Need Not Prevent RP PERIOPERATIVE ASPIRIN use should not be considered an absolute contraindication to radical prostatectomy (RP), according to investigators.

Using the Premier Hospital Database, an all-payer hospital discharge database in the United States, Matthew D. Ingham, MD, and colleagues from Harvard

Medical School in Boston studied 157,674 patients undergoing RP (4400 who continued on aspirin and 153,274 not taking aspirin). Perioperative aspirin use was not significantly associated with in-hospital complication rates. Although the 90-day rates of myocardial infarction, major complications, and readmission were

higher among aspirin users, “we suspect this is likely the result of an uncaptured confounder—a known weakness of discharge datasets,” they concluded.

Aspirin users were older, less healthy, and more likely to receive an open RP than non-aspirin users, the investigators noted. n

20 Renal & Urology News

■ GUCS 2018, San Francisco

MARCH /APRIL 2018 www.renalandurologynews.com

2018 Genitourinary Cancers Symposium, San Francisco

MRI Predicts Adverse Pathologic PCa Features MULTIPARAMETRIC magnetic resonance imaging (mpMRI) can accurately predict adverse pathologic features at the time of radical prostatectomy (RP) for localized prostate cancer, a study found.

That conclusion is based on a study of 30 patients with localized prostate cancer (PCa) who had mpMRI scans prior to RP. Samarpit Rai, MD, a urology resident at the University of Louisville School of

Medicine in Kentucky, and colleagues compared mpMRI findings with postoperative pathologic specimens. The investigators analyzed the sensitivity, specificity, positive ­predictive value (PPV), and

negative predictive value (NPV) of preoperative mpMRI for adverse pathologic features: extracapsular extension (ECE), seminal vesicle invasion (SVI), lymph node involvement (LNI), and high-risk Gleason score (Gleason 8 or higher).

Patients had a median age and preoperative PSA level of 62.5 years and 8.5 ng/ mL, respectively. Of the 30 patients, 17 had ECE, 5 had SVI, 5 had LNI, and 15 had high-risk Gleason score (4+3, tertiary pattern 5, 4+4 or higher). The sensitivity, specificity, PPV, and NPV of mpMRI for ECE was 64.7%, 91.6%, 91.6%, and 66.6%, respectively. The values were 60%, 96%, 75%, and 92.3%, respectively, for SVI and 100%, 96%, 83.3%, and 100%, respectively, for LNI. For high-risk Gleason score, the sensitivity, specificity, PPV, and NPV were 94.4%, 66.6%, 80.9%, and 88.9%, respectively.

The PPV and NPV for high-risk Gleason score were 80.9% and 88.9%, respectively.

It is known that patients with PCa and adverse pathologic features, such as ECE, LNI, and high-risk Gleason score have a higher rate of biochemical recurrence after treatment. Dr Rai noted that mpMRI is an important and emerging imaging tool for determining adverse pathologic features and guiding treatment. “This could provide assistance in the selection of patients appropriate for active surveillance vs active treatment and aid in determining their prognosis,” he said.

He noted that there is significant inter-observer variability among radiologists in the interpretation of MP-MRI, which is a limitation of the study.

The new study builds on accumulating evidence that MP-MRI can improve diagnostic accuracy. For example, a retrospective study published in the European Journal of Radiology (2018;98:107-112) found that mpMRI had a high diagnostic accuracy for SVI on histopathology. The study, which included 527 men who underwent RP, revealed that MP-MRI had a sensitivity, specificity, PPV, and NPV for SVI detection of 75.9%, 94.7%, 62%, and 97%, respectively. n

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Renal & Urology News 21

Meropenem-vaborbactam Found Superior for cUTI MEROPENEM-vaborbactam, a combination carbapenem/beta-lactamase inhibitor, is more effective than piperacillin-tazobactam at treating complicated urinary tract infections (UTIs), according to a new study.

The phase III randomized TANGO I (Targeting Antibiotic Non-Susceptible Gram-Negative Organisms) trial compared the 2 antibiotic therapies in adult patients with complicated UTIs, including acute pyelonephritis. The trial had 2 primary endpoints. Overall success, defined overall success as a composite of clinical cure or improvement and microbial eradication, was the primary outcome for FDA criteria. Microbial eradication at test-of-cure visit was the primary endpoint for European Medicines Agency (EMA) criteria.

The FDA primary endpoint occurred in 98.4% of patients ­receiving ­meropenem-vaborbactam compared

Urolithiasis Ups Bladder CA Risk PATIENTS WITH a history of urinary stones are at increased risk of bladder cancer, a new meta-analysis suggests.

Based on pooled data from 13 studies, stone formers had nearly 2-fold greater odds of bladder cancer compared with non-stone-formers, Guo Wenbin, MD, of the Third Affiliated Hospital of Southern Medical University in Guangzhou, China, and collaborators reported in Urolithiasis.

The odds of bladder cancer were 2-fold higher among patients with a history of bladder stones and 1.4-fold higher among those with a history of kidney stones.

Despite heterogeneity among studies, results held in subgroup analyses by gender, geographic region, and study type. A history of urinary stones was associated with 3-fold greater odds of bladder cancer among women compared with 2-fold greater odds among men.

The investigators posited that urinary calculi cause chronic irritation and infections that promote development of neoplastic cells. n

with 94% who received piperacillintazobactam, Keith S. Kaye, MD, MPH, of the University of Michigan Medical School in Ann Arbor, and colleagues reported in JAMA (2018;319:788-799).

The EMA primary endpoint was met in 66.7% of meropenem-vaborbactam recipients vs 57.7% of piperacillin-­

tazobactam recipients. The differences between the treatment arms were statistically significant.

Of 550 patients randomized, 545 (272 in meropenem-vaborbactam group and 273 in piperacillin-tazobactam group) received at least 1 dose of study drug.

The meropenem-vaborbactam dosing

regimen was 2g/2g over 3 hours; the piperacillin-tazobactam dosing regimen was 4g/0.5g over 30 minutes. The vast majority of both treatment arms had Enterobacteriaceae species as a baseline pathogen: 85.6% of the meropenemvaborbactam group and 84.6% of the piperacillin-tazobactam group. n

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S:14”

Aspirin Found Effective for Erectile Dysfunction ANTIPLATELET treatment with aspirin could be a new treatment option for vasculogenic erectile dysfunction (VED), particularly for men with a high mean platelet volume (MPV), according to investigators.

In a prospective randomized doubleblind placebo-controlled study, Zeki Bayraktar, MD, and Selami Albayrak, MD, of Istanbul Medipol University in Turkey, found that therapy with 100 mg/day of aspirin for 6 weeks was associated with significant improvement in erectile function compared with placebo among men with VED and a high MPV. “Large platelets are metabolically and enzymatically more active than small platelets and produce more thromboxane, known as the most potent vasoconstrictor agent,” the investigators explained.

Some recently published studies have found a relationship between high MPV values and VED, but no previous study has examined the efficacy of antiplatelet therapy on VED, they noted.

r­ecipients (a 2-point increase), a significant difference between the groups, Drs Bayraktar and Albayrak reported online in International Urology and Nephrology.

At baseline, the proportions of patients who answered yes to SEP2 and SEP3 were similar in both study

arms: 51.6% and 31.6%, respectively, in the aspirin group and 50% and 31.2% in the placebo group. At the end of treatment, the proportions answering yes to SEP2 and SEP3 were significantly higher in the aspirin than placebo group (88.3% and 78.3% vs 59.3% and 43.5%).

“Aspirin is an effective and safe therapeutic option for patients with VED, especially for patients with a high MPV,” the authors concluded.

Darshan P. Patel, MD, of the Division of Urology at the University of Utah School of Medicine in Salt Lake City, who was not involved in the new

Aspirin 100 mg/day for 6 weeks improved vasculogenic erectile dysfunction.

The investigators evaluated erectile function using the International Index of Erectile Function (IIEF-EF) and 2 yes-or-no questions on the Sexual Encounter Profile (SEP) instrument: SEP2 (“Were you able to insert your penis into partner’s vagina?”) and SEP3 (Did your erection last long enough for you to have successful intercourse”?).

The aspirin and placebo groups included 120 and 64 patients, respectively, with mean ages of 48.3 and 47.7 years. To be included in the study, patients needed to have an MVP above 11 fL. According to the assay kits used to measure MVP, the normal range for MPV is 7.8 to 11 fL, the authors noted.

The aspirin and placebo groups had similar mean MVP values (11.57 and 11.54 fL respectively).

The mean baseline IIEF-EF scores in the aspirin and placebo groups were similar (14.1 and 14.3, respectively). At the end of treatment, the mean IIEF-EF score was 21.3 in the aspirin group (a 7.2-point increase) compared with 16.3 among placebo

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Renal & Urology News 23

S:14”

study, said the results of the investigation by Drs Bayraktar and Albayrak should be interpreted with caution.

“The study excluded many patients at the highest risk of vasculogenic ED— patients with diabetes, hypertension, coronary artery disease,” said Dr Patel, who participated in a previous study showing no association between use of nonsteroidal anti-inflammatory drugs and ED among patients in the

Prostate Cancer Prevention Trial (BJU Int. 2016;117;500-506). “The unequal allocation (2:1 randomization) harbors certain threats to the internal validity of a confirmatory study. Although the study adds to the growing body of evidence linking endothelial dysfunction to ED, the results must be reproduced prior to drawing conclusions regarding aspirin therapy for prevention and treatment of ED.”

A previous randomized double-blind study published in Bipolar Disorders (2013;15:650-656) found that aspirin improves lithium-related sexual dysfunction in men with stable bipolar affective disorder (BAD). In that study, 32 men with BAD who had been on lithium maintenance therapy were randomly assigned to take aspirin 240 mg/day or placebo for 6 weeks. Thirty patients, 15 in each group, completed the study.

Investigators used the IIEF to assess sexual symptoms at baseline and week 3 and 6. At the end of 6 weeks, the aspirin group showed significantly greater improvement in the total and erectile function domain scores on the IIEF than the placebo group. In addition, 12 (80%) patients in the aspirin group and 3 (20%) patients in the placebo group met the criteria of minimal clinically important change, the authors reported. n

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Elevated SUA Trajectories Raise ESRD Risk in CKD PATIENTS WITH CHRONIC kidney disease (CKD) and elevated serum uric acid (SUA) trajectories are at increased risk of end-stage renal disease (ESRD) and death, according to new study findings.

Chin-Chi Kuo, MD, and collaborators from China Medical University

Hospital in Taiwan, assessed data from 5090 participants (aged 20–90 years) in their pre-ESRD registry. Using serial measurements of SUA and group-based T:7.875” trajectory modeling, the team described S:7” 4 uric acid trajectories: low, medium, medium-high, and high. A hyperuricemia cutoff of 7.5 mg/dL separated

the low and medium patterns from the medium-high and high patterns.

Of the patients in the cohort, 948 progressed to ESRD and 472 died at rates of 57.9 and 28.7 cases per 1000 person-years, respectively, according to results published in Nephrology Dialysis Transplantation. Compared

with patients who had a low uric acid trajectory, individuals with moderate, moderate-high, and high trajectories had approximately 1.9-, 2.5-, and 2.8fold greater risks of ESRD, respectively, and 1.4-, 2.0-, and 4.5-fold greater risk of all-cause mortality, respectively. The researchers adjusted for renal function, competing risks of death, and other confounders. Patients with CKD who did not take urate-lowering agents at baseline appeared more likely to progress to ESRD. “In conclusion, the results of this study demonstrate the importance of SUA as a risk factor of all-cause mortality and progression to ESRD among CKD patients. Adequate experimental and empirical evidence is urgently required to assess whether SUA is an independent therapeutic target,” Dr Kuo and his colleagues wrote.

A high vs low trajectory raises the risk of ESRD by nearly 3-fold.

S:10

T:10.75”

A 2017 study published online in the American Journal of Kidney Diseases also associated hyperuricemia with an increased risk of renal failure among patients with CKD stage 2 to 4. The study, by Anand Srivastava, MD, MPH, of Northwestern University in Chicago, and colleagues, found that each 1 standard deviation increase in baseline uric acid was associated with a 40% increased risk of ESRD among patients with an estimated glomerular filtration rate of 45/min/1.73 m2 or above.

The investigators also found a J-shaped curve between uric acid levels and allcause mortality.

At the Kidney Week 2015 conference, researchers reported on a 6-year population-based cohort study showing that individuals in the highest quartile of SUA (above 7.3 mg/dL) had a 3.4-fold increased risk of ESRD compared with those in the lowest quartile (less than 5.2 mg/dL) after adjusting for potential confounders. The study, which enrolled 23,712 individuals older than 20 years, also found that those with an SUA level of 7 mg/dL or higher had a 5.7-fold increased risk of ESRD compared with individuals who had a lower level. In addition, each 1 mg/dL increase in SUA was associated with a 2.4 mL/min/1.73 m2 decline in eGFR. n

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Renal & Urology News 25

■ Special to Renal & Urology News

Implementation of Dashboard Brings CROWNWeb Reporting Up to Speed The Centers for Medicare & Medicaid Services introduced a new feature to facilitate timely submission of required data to its national ESRD patient registry and quality measuring reporting system

Summary: After the national release of CROWNWeb in 2012, the Centers for Medicare & Medicaid Services (CMS) reviewed ways to support data reporting needs. This article provides an overview of the process CMS followed to implement a dashboard in its CROWNWeb system, and how this new feature is helping to improve users’ ability to submit required data within a timely manner.

BY ONIEL DELVA, BA, CTT+ COMPUTERS MAKE the world “go ‘round.” Decades after the birth of the World Wide Web, Pew Research Center reported that 73% of adults living in the United States own and use desktop and/or laptop computers daily.1 We use computers and computer programs to complete virtually everything—from paying bills to supporting health professionals’ efforts to keep those suffering from end stage renal disease (ESRD) alive by monitoring and mixing dialysate in their blood to remove unwanted waste products.

According to information technology journal The Data Center, the vast majority of data is managed electronically, and the global volume of electronically stored data is doubling every 2 years.2 With this knowledge, developers understand that the quality and longevity of a computer program is determined by its architecture.3 How well was the system designed? How does it help solve problems? How can the system be modified to support growing data submission needs?

In 2012, the Centers for Medicare & Medicaid Services (CMS) released CROWNWeb, the agency’s national ESRD patient registry and quality measuring reporting system, to enable Medicare-certified dialysis facilities to

meet Section 494.180(h) of the 2008 updated Conditions for Coverage for ESRD Dialysis Facilities. Using CROWNWeb, approved personnel submit administrative and clinical data directly to CMS in real time. For 5 years, over 20,000 authorized users at nearly 7,000 Medicare-certified dialysis facilities and select transplantation centers have submitted admit/ discharge data, treatment records, and forms for the more than 660,000 patients being treated for kidney failure in the United States.

During CROWNWeb’s development, CMS recognized that this system’s architecture held great importance, as it would lay the framework for the system’s ability to be modified in order to support new goals to optimize health outcomes, endeavors to promote high-quality patient care, efforts to provide reliable data to ESRD research organizations, as well as attempts to meet facilities’ data maintenance needs.

Over the years, CMS has implemented a number of updates and enhancements to its CROWNWeb system. The agency updated its account registration process to include extra layers of security, while simplifying the process users would follow to access all CMS QualityNet databases. CMS revamped CROWNWeb’s Clinical screen to remove data elements that are no longer relevant, as well as included new elements such as pain assessment and clinical depression screening and follow-up. CROWNWeb was updated in 2015 to support the entry of codes from the tenth revision of the International Classification of Diseases (ICD-10) on the agency’s CMS2728 ESRD Medicare Entitlement and/or Patient Registration form.

CMS recently continued with its CROWNWeb enhancement efforts

in June 2017 by incorporating a new Facility Dashboard, which allows users to better review, and work toward submitting, missing and past due data.

What Is a Dashboard?

In information technology, a dashboard is a user interface that helps organize and present information in a way that is easy to read.4 As data volumes increase, organizations have adopted the use of dashboards to help make sense of their data.5 Organizations build dashboards with the hope that they can turn mountains of data into actionable insights.5 Dashboards can take multiple forms, but one element is common among all: the data is the most important aspect.

The Formation of CROWNWeb’s Facility Dashboard While CMS implemented its CROWNWeb Facility Dashboard in June 2017, initial discussions for this feature began in 2014 after CMS assessed suggestions provided by users and members of the application support team. As with any system-related release, the CROWNWeb Facility Dashboard went through a series of testing and analysis as it went from proposal to production.

After years of development work, CMS finalized its Facility Dashboard to serve as a means of providing users direct access to a comprehensive list of items requiring submission to CROWNWeb.

How the CROWNWeb Facility Dashboard Works After logging in to CROWNWeb, users are immediately taken to the Facility Dashboard, and can access detailed information in 9 sections (Table 1): Each section includes a count that allows users to identify if data submission is due or past due for patients who are located at a facility within their approved scope. After seeing a count for a section, users are able to click the number displayed to be presented with a records page that provides a list of the patients who are in need of submission in that section.

Users are then able to click on a system-generated CROWNWeb Unique Patient Identifier (UPI) to be taken directly to that data submission element in a selected patient’s records.

Users can work to submit the necessary information, and then return to the CROWNWeb Facility Dashboard to complete additional requirements.

The system refreshes within minutes to remove resolved items from the counts of unresolved items.

CROWNWeb Data Reporting Pre and Post Facility Dashboard The CROWNWeb Facility Dashboard uses CMS-determined submission periods to govern the dates by when facilities should submit their data in CROWNWeb. Some data elements such as the need to verify patient admit continued on page 26

TABLE 1. CROWNWeb Facility Dashboard Sections Form 2728

System Discharges

Pain Assessments

Form 2746

PART

Form 2744

Notifications & Accretions

Clinical Depression Screenings

Clinical Data

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TABLE 2. CMS-2728 Data Quality Goals May 2017

Admission within 5 Days

69%

67%

90%

Initial CMS-2728 within 10 Days (New)

22%

21%

50%

Initial CMS-2728 within 45 Days (Due)

86%

89%

90%

CMS-2746 within 14 Days

60%

60%

90%

System Discharges/GAP Patients

4,287

4,142

0

Notification & Accretion Alerts Resolved within 15 Days

16,511

13,498

90% resolved

PART Every 30 Days

96%

95%

100%

and discharge activities and modalities monthly, and the need to complete a CMS-2746 Death Notification form within 2 weeks of a patient’s death, follow historical submission deadlines that were in place prior to CROWNWeb. Clinical data submissions include labs and treatment information for hemodialysis and peritoneal dialysis patients, as well as vascular access information, and are due monthly.

While most data elements in CROWNWeb have pre-determined deadlines, CMS identified the importance of creating a set of guiding principles that would help specify when users should complete certain tasks, such as when to admit or discharge a patient in CROWNWeb, by creating CROWNWeb Data Management Guidelines. Furthermore, in early 2016, CMS established Data Quality Goals that focus on improving the rate of submission of select elements in a timely manner. As part of the Data Quality Goals, CMS set submission percentages that the agency wants facilities to strive to achieve within a designated timeline for select data elements. In its second year, CMS used data from 2016 to help set the baseline for the agency’s 2017–2018 goals. CMS uses the submission timelines called out in the CROWNWeb Data Management Guidelines to identify if these targets are being met.

Data supporting CMS’ Data Quality Goals shows that the submission rate of CMS-2728 forms improved slightly from May 2017 to June 2017. CMS identified a slight improvement from 86% of CMS-2728 forms being completed within 45 days of after a patient begins treatment to 89% (Table 2).

Furthermore, the data reveal a substantial improvement in the number of Notification and Accretion alerts resolved within 15 days, demonstrating

June 2017

June 2018 Goal

Category

a drop from 16,511 unresolved alerts in May 2017 to 13,498 in June 2017.

For More Information CMS plans to continue to monitor facility needs and the possibility of enhancing the Facility Dashboard section in CROWNWeb to incorporate new data reporting elements. For more information on CROWNWeb and the system’s features, visit the My CROWNWeb website at http://mycrownweb.org/, or visit the CMS CROWNWeb website at https://www.qualitynet.org/ and click on the ESRD tab. n The work on which this publication is based was performed under Contract Number HHSM-500-2015-00511G, titled “CROWNWeb Outreach, Com­ mu­ni­ca­tions, and Training,” funded by the Centers for Medicare & Medicaid Services, Department of Health and Human Services, Janis Grady, CMS COR. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. government.

REFERENCES: 1. Anderson M (2015, October 26). Technology Device Ownership: 2015. Pew Research Center.

Retrieved September 26, 2017 from http://www. pewinternet.org/2015/10/29/technology-deviceownership-2015/.

2. LaChapelle C. (2016, March 10). The Cost of Data Storage and Management: Where Is It Headed in 2016? The Data Center. Retrieved September 26, 2017 from http://www.datacenterjournal.com/costdata-storage-management-headed-2016/.

3. Northrop L. (2003). The Importance of Software Architecture. Carnegie Mellon University. Retrieved September 26, 2017 from http://csse.usc.edu/ GSAW/gsaw2003/s13/northrop.pdf.

4. Rouse M. (2005, September). Definition: Dashboard.

Tech Target. Retrieved September 26, 2017 from http://searchcio.techtarget.com/definition/ dashboard.

5. Stangarone J. (2016, June 29). The 3 most important aspects of a business dashboard. Retrieved September 26, 2017 from http://www.mrc-productivity.com/ blog/2016/06/the-3-most-important-aspects-of-abusiness-dashboard-2/.

Learning Difficulties More Common in Kids with CKD

BY NATASHA PERSAUD CHILDREN WITH CHRONIC kidney disease (CKD) may have more intellectual and academic difficulties than other children, according to new research findings.

Kerry Chen, MBBS, of The Children’s Hospital at Westmead in Sydney, Australia, and the University of Sydney’s Centre for Kidney Research, and colleagues performed a systematic review of 34 observational studies including 3086 children (younger than 21 years) residing in 9 countries. Of the children with CKD, 86% had mild-tomoderate stage disease, 4.7% received dialysis, and 9.8% underwent kidney transplants. Eighteen studies were used for meta-analyses. The overall risk of bias among the studies was high, according to the investigators.

According to results published online ahead of print in the Clinical Journal of the American Society of Nephrology, the global cognition of children with CKD was low-average as assessed by the full-scale intelligence quotient (FSIQ). The mean difference in FSIQ was 10.5 points lower for children and adolescents with CKD compared with the general population. By subgroup, scores were 9.39, 11.2, and 16.2 points lower for kids with predialysis CKD, those with kidney transplants, and those on dialysis, respectively. Dialysis patients scored 11.2 and 10.1 FSIQ points lower than children with mild-to-moderate CKD or kidney transplants, respectively. With regard to executive function and memory (verbal and visual), pediatric CKD patients overall scored lower than the general population.

Academically, CKD patients scored 15.7 to 1.22 points lower in mathematics, 9.04 to 0.17 points lower in reading, and 14.2 to 2.53 points lower in spelling. Children with CKD had difficulty in holding information and shifting from 1 stimulus to another, the authors explained. Despite fewer cognitive skills, students with CKD could regulate their behavior.

“Clinically, scores at least one SD [standard deviation] lower in overall intelligence and domain-specific cognitive domains place children at increased risk of poor academic performance at school, reduced quality of life and poor mental health with potential implications for vocational attainment and financial independence as they

transition into adulthood,” Dr Chen and his collaborators warned.

Several possible mechanisms might underlie the connection between CKD and intellectual impairment. “Firstly, increased plasma levels of uremic solutes arising from kidney disease may impair synaptic development,” Dr Chen explained in a news release from the University of Sydney. “Dialysis may also lead to cognitive impairment through rapid changes in blood pressure.”

Further, the pathologic effects associated with end-stage renal disease, such as anemia, hypertension, and malnutrition, may reduce cognitive function among children on dialysis compared with other CKD stages.

Cognitive skills are diminished vs the general population, meta-analysis shows.

He noted that treatments for CKD may compromise academic achievement. The frequency of sleep disturbances in kids with CKD may result in poor concentration, excessive daytime sleepiness, and lower academic performance.

In addition, Dr Chen observed, “the interactions of complex medication routines and strict dialysis cycles may decrease attentional control, working memory, and executive function-cognitive domains that are important to children’s ability to acquire, understand, and retain information in social and educational environments.”

Lastly, he said, ongoing dialysis sessions and recovery from transplant surgeries may decrease the amount and regularity of time spent in the classroom, “with chronic absenteeism potentially preceding loss of interest, withdrawal, and poor school progression.”

In an accompanying editorial, Lori M. Hartwell, president of Renal Support Network in Glendale, California, and a former pediatric CKD patient, observed: “This is a valuable review of several existing studies; a serious reminder that children and adolescents with chronic kidney disease face medical, psychological, and social barriers to learning; and a clear indication that interventions designed to be responsive to patient needs are necessary.” n

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Single PSA Screening Has No Effect on PCa Mortality Finding is based on a study of men with a median follow-up of 10 years s­tandard practice without screening, there was no significant difference in prostate cancer mortality after a median follow-up of 10 years but the detection of low-risk prostate cancer cases increased,” the authors concluded. “Although longer-term follow-up is under way, the findings do not support single PSA testing for population-based screening.”

© BSIP / UIG / GETTY IMAGES

SINGLE PSA screening tests make no significant difference in prostate cancer mortality, according to a new study.

As part of the Cluster Randomized Trial of PSA Testing for Prostate Cancer (CAP), Richard M. Martin, PhD, from the University of Bristol in the United Kingdom, and colleagues randomly assigned 573 primary care

Single PSA screenings led to a rise in PCa diagnoses, but did not lower PCa death risk.

practices in the United Kingdom to offer men aged 50 to 69 years an invitation to a single PSA test (271 practices) and a control group that did not offer PSA testing (302 practices). After a median follow-up of 10 years, 549 of the 189,386 men in the PSA screening group (0.30 per 1000 person-years) and 647 of 219,439 men in the control group (0.31 per 1000 person-years) died from PCa, a non-significant betweengroup difference in mortality rate, Dr Martin’s team reported in JAMA (2018;319:883-895).

With respect to all-cause mortality, 25,459 deaths occurred in the screening group (13.74 per 1000 person-years) and 28,306 deaths occurred in the control arm (13.51 per 1000 person-years), a non-significant difference in death rate.

PCa was diagnosed in a significantly higher proportion of patients in the screening vs control arm (4.3% vs 3.6%), however.

“Among practices randomized to a single PSA screening intervention vs

Of the 189,386 men in the screening arm, 75,707 (40%) attended a PSA testing clinic and 67,313 (36%) underwent PSA testing. Of 64,436 men with a valid PSA test result, 6857 (1150 had a PSA level of 3 to 19.9 ng/mL. Among these men, 5850 underwent a prostate biopsy.

The study provides new evidence that complements published trials such as the European Randomized Study of Screening for Prostate Cancer (ERSPC) and the Prostate, Lung, Colorectal, and Ovarian Cancer Screening (PLCO) trial, the authors noted. Both trials involved repeated PSA testing at intervals of 1, 2, or 4 years. The CAP trial was designed to determine the effects of a low-intensity, single invitation PSA test and standardized diagnostic pathway on PCa-specific and all-cause mortality while minimizing overdetection and overtreatment.

“It was an interesting and well-conducted study with unsurprising results,” commented Eric Klein, MD, Chairman of the Glickman Urological and Kidney

Institute at Cleveland Clinic, who was not involved in the new study.

The main concern it raised is that even a single PSA results in overdetection of low-grade cancers, but the trial did not account for the substantial increase in active surveillance for such patients, which substantially reduces the harms of overdetection, Dr Klein told Renal & Urology News.

“One of the limitations of the study was that it was analyzed on an intent-toscreen basis, just as the initial analysis of the PLCO was done,” Dr Klein pointed out. “A recent re-analysis of the PLCO [trial] comparing men who actually got screened vs those not screened showed the same value to screening that was demonstrated in the ERSPC. It would be interesting to look at the data in this trial in the same fashion. There is also a lot of data showing that a single PSA [screening] at age 50 predicts lifetime risk of prostate cancer. It would be interesting to see if that held true in this trial as well.”

The negative results of the PLCO trial, he said, are negated by the high drop-in rate in the control arm. A reanalysis of screened vs unscreened men in the PLCO trial showed a similar benefit to screening as in the ERSPC. Furthermore, he noted, the benefit of screening should not only be measured in reductions in mortality, but also in reductions in the rate of metastatic disease, which has a significant treatment burden in terms of morbidity and cost.

“The benefit in reducing metastatic disease demonstrated in those screened in the ERSPC was substantial—around 30%—and is often overlooked in the debate on screening,” Dr Klein said.

“The weight of the data supports that regular PSA screening both reduces the risk of dying of prostate cancer and the risk of getting metastatic disease. Much of the harm from screening is mitigated by the use of active surveillance for low-grade cancers. Newer modalities such as genomic testing, which allows for direct assessment of the biological potential of the tumor, and mpMRI [multiparametric magnetic resonance imaging], which reduces the risk of biopsy under sampling, promise the development of more precise management strategies for each patient.” n

Prior Stroke Found to Raise Risk of UUI PREVIOUS STROKE or transient ischemic attack (TIA) may be a risk factor for urgency urinary incontinence (UUI), according to a British study of older individuals. In addition, findings suggest that severe UUI has a distinct presentation with more specific contributory mechanisms than milder UUI. In a study of 1762 participants aged 68 years, individuals who had a previous stroke or TIA at age 60 to 64 years had a significant 2-fold higher risk of UUI, in a fully adjusted model, Alex Tsui, of the MRC Unit for Lifelong Health and Ageing at UCL, London, and colleagues reported online ahead of print in BJU International. As in previous studies, higher body mass index (BMI) was linked with an increased risk of UUI. Each standard deviation increment in BMI was associated with a significant 19% higher odds of UUI. Female sex and co-presentation with stress urinary incontinence were associated with a significant 4-fold and 1.8-fold increased odds of UUI, respectively.

Other risk factors include female sex and increasing body mass index.

Study participants were part of a Medical Research Council National Survey for Health and Development birth cohort. All were born in 1 week in March 1946. At a home or clinic visit, a research nurse collected information on vascular risk factors when the individuals were aged 60 to 64 years. The prevalence of UUI at age 68 was 19% among women, and 12% among men.

The associations between UUI and these risk factors were stronger with severe UUI. Prior stroke or TIA was associated with a 3.6 times greater relative risk of severe UUI symptoms. The investigators found no corresponding association with mild UUI. Hypertension at age 60 to 64 years was independently associated with a significant 1.6-fold higher risk of UUI in men, but was not associated with UUI risk in women.

Among women, the study found no association between UUI symptoms and menopause or use of hormone replacement therapy. n

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PCa drugs cut mets risk continued from page 1

investigators observed a non-significant trend toward improved overall survival.

Dr Small pointed out that although ­subsequent FDA-approved treatment was administered to 80% of the patients in the placebo group, the apalutamide arm still had an improvement in time to symptomatic progression as well as a 51% improvement in second progression-free survival (time from randomization to investigator-assessed disease progression during the first subsequent therapy for metastatic castration-­resistant disease or death from any cause).

“Treatment with apalutamide was generally well tolerated, with no impact on quality of life scores and with low rates of discontinuation due to treatment-related adverse events,” Dr Small said. “Overall, these data suggest that apalutamide should now be considered a new standard of care for men with high-risk non-metastatic castrationresistant prostate cancer.”

The study, which was published online ahead of print in the New England Journal of Medicine, included 1207

CN ups survival odds continued from page 1

with papillary h ­ istology may improve ­survival ­compared with not undergoing the surgery.

Dr Bhindi’s team compared overall survival (OS) between 6731 patients treated initially with CN (median age 62 years) and 8337 patients who received targeted therapy first (median age 60 years). At 6 months after initial CN, 48% received targeted therapy, with 15.3% of patients having died after initial CN prior to receiving targeted therapy. At 6 months following initial targeted therapy, 4.7% underwent CN, with 44.9% having died after initial targeted therapy prior to undergoing CN. In an analysis of patients from each

Combo for mRCC continued from page 1

and sunitinib block ­vascular endothelial growth factor. Of the 915 patients, 362 had PD-L1 positive tumors.

After a median survival follow-up of 15 months, the median PFS for the entire study population was 11.2 months in the atezolizumab-bevacizumab group and 8.4 months among sunitinib recipients. In the PD-L1 positive group, median PFS was 11.2 months in the

patients whose cancer no longer responding to androgen-deprivation therapy (ADT) and were at high risk of metastasis based on a PSA doubling time (PSADT) of 10 months or less. All patients continued to receive ADT. The median PSADT at study entry was about 4.5 months. Investigators randomly assigned 806 patients to receive apalutamide 240

Apalutamide could be a new standard of care for men with high-risk nmCRPC. mg once daily and 401 to receive placebo.

The primary end point was MFS, defined as the time from randomization to first radiographic distant metastasis or death.

The median MFS was 40.5 months in the apalutamide group compared with 16.2 months in the placebo arm. At a median follow-up of 20.3 months, 61% of apalutamide-treated patients and 30% of placebo recipients remained on treatment. Rates of discontinuation due to adverse events were 10.7%

group matched by propensity score, the investigators found that initial CN was associated with significantly improved survival compared with initial targeted therapy (median 16.5 vs 9.2 months). In the overall cohort, patients who underwent initial CN had a 38% decreased risk of death compared with those who received initial targeted therapy.

Among patients with clear-cell and non-clear cell RCC, those who underwent initial CN had a 39% and 27% decreased risk of death, respectively.

In a conditional 6-month landmark analysis, Dr Bhindi and his colleagues stratified patients who received initial targeted therapy by whether or not subsequent CN was performed. Initial CN was associated with a 45% decreased risk of death compared with targeted

atezolizumab-bevacizumab group compared with 7.8 months in the sunitinib arm. In the overall study population, patients who received atezolizumabbevacizumab had a significant 17% decreased risk of progression compared with sunitinib-treated patients. In the PD-L1 positive population, patients in the atezolizumab-bevacizumab group had a 26% decreased risk of progression compared with sunitinib recipients.

Treatment-related grade 3-4 adverse events occurred less frequently in the

and 6.3% in apalutamide and placebo groups, respectively.

Dr Small’s team concluded that their results support the addition of apalutamide to ADT for men with nmCRPC.

PROSPER trial results In the randomized, double-blind phase 3 PROSPER trial, men with non-metastatic CRPC who received enzalutamide in addition to ADT had a prolonged median MFS—the study’s primary end point, which was defined as the time from randomization to radiographic progression or death within 112 days of treatment discontinuation—compared with those who received ADT plus placebo (36.6 vs 14.7 months), reported lead investigator Maha H. Hussain, MD, Deputy Director of the Robert H. Lurie Comprehensive Cancer Center at Northwestern University in Chicago. In men with non-metastatic CRPC and rapid PSA doubling time, “enzalutamide resulted in a clinically meaningful and significant 71% reduction in the relative risk of developing metastatic castration-resistant prostate cancer,” Dr Hussain told attendees.

In addition, enzalutamide treatment was associated with a significantly therapy alone. Patients who had initial targeted therapy followed by CN had a 48% decreased risk of death compared with targeted therapy alone.

“Given a greater likelihood of receiving multimodal therapy and an associated

­ rolonged time to first use of a new antip neoplastic agent (median 39.6 vs 17.7 months) and time to PSA progression (median 37.2 vs 3.9 months) compared with placebo. Enzalutamide was associated with a significant 79% decreased risk of requiring a new antineoplastic agent and 93% decreased risk of PSA progression compared with placebo. As of June 2017 (cutoff date), median duration of treatment was 18.4 months in the enzalutamide group compared with 11.1 months in the placebo arm. As of February 5, 61% of patients randomly assigned to enzalutamide were active on treatment compared with 28% in the placebo arm, according to Dr Hussain.

At first interim analysis with a median follow-up time of about 22 months, there was a 20% reduction in the relative risk of death with enzalutamide vs placebo.

The study included 1401 men with a PSA doubling time of 10 months or less and a PSA level of 2 ng/mL or higher.

All men continued receiving ADT. Investigators randomly assigned 933 patients to receive enzalutamide 160 mg and 468 to receive placebo. The enzalutamide and placebo arms had median ages of 74 and 73 years, respectively. n

OS benefit, these data support CN as the initial approach for mRCC in appropriate surgical candidates,” said Dr Bhindi, a urologic oncology fellow. “However, given patients who received CN after tar-

geted therapy also had favorable survival, the debate on sequencing is far from over. More work is needed to optimize the delivery of multimodal approaches.”

For the other study, Dr Graham and his team used the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) database to identify 353 patients with papillary mRCC. Of these, 244 underwent CN and 109 did not. The CN group had significantly longer survival (median 16.3 vs 8.6 months).

After adjusting for IMDC risk factors, CN was associated with a significant 38% decreased risk of death, said Dr Graham, who presented study findings in an oral presentation. After adjusting for IMDC risk factors, age, and presence of bone metastases, CN was associated with a significant 45% decreased risk of death. n

atezolizumab-bevacizumab than sunitinib group (40% vs 54%).

“These results support atezolizumab plus bevacizumab as a first-line treatment option for patients with PD-L1 positive advanced RCC,” Dr Motzer told attendees.

For an aggressive cancer such as mRCC, where less than 20% of patients survive 5 years after diagnosis, a 3.5month longer PFS, given the tolerability of the combined regimen, is an important development, according to Dr Motzer.

“The study that Dr Motzer presented represents an important breakthrough in kidney cancer therapy,” said Sumanta K. Pal, MD, an American Society of Clinical Oncology expert who moderated a pre-symposium press conference at which Dr Motzer described his findings. He noted that the combination therapy achieved a higher rate of complete response than sunitinib.

“Achieving a complete response … is really the highest bar that we can strive for in this setting,” he said. n

Initial CN vs initial targeted therapy was associated with a 38% lower death risk.

www.renalandurologynews.com MARCH /APRIL 2018

Renal & Urology News 31

Ultra-low Contrast Volume May Lower CIN Risk USE OF ULTRA-LOW contrast volume is a safe, feasible, and effective way to prevent contrast-induced nephropathy (CIN) in patients with advanced chronic kidney disease (CKD) undergoing coronary procedures, researchers in Israel concluded.

The finding is from a prospective study of 30 patients undergoing coronary angiography or percutaneous coronary intervention (PCI). All patients had an estimated glomerular filtration rate below 45 mL/min/1.73 m 2 (mean 31.8 mL/min/1.73 m 2). The median contrast volume was 13 mL for diagnostic coronary angiography, with an additional 13 mL for PCI. Starting 12 hours before their procedure, all patients received prehydration with intravenous isotonic saline at a rate of 1 mL per kilogram of body weight per hour, or 0.5 mL per hour for patients who had severely reduced

left ­ventricular function. The primary endpoint was development of CIN, defined as a 25% or greater increase in serum cystatin C or creatinine 48 hours following the coronary procedure. The same interventional cardiologist performed all the procedures.

A median contrast volume of 13 mL was injected for diagnostic coronary angiography.

At 48 hours post-procedure, 3 patients (10%) had a 25% or greater increase in serum cystatin C levels, but no patient had a 25% or greater increase in serum creatinine, Zach Rozenbaum, MD, of Tel Aviv Sourasky Medical Center and Sackler Faculty of

Medicine, Tel Aviv University, and colleagues reported in Nephron Clinical Practice. After a follow-up period of 6 months, no patient required renal replacement therapy or unplanned coronary intervention, they noted.

“The current study is the first to demonstrate the feasibility and safety of coronary angiographic and PCI with ultra-low contrast volume in consecutive real-life patients with advanced chronic kidney disease,” the authors observed.

The investigators concluded that the use of ultra-low contrast volume may increase the use of PCI in high-risk coronary patients with CKD. In addition, they noted that since cystatin C was more sensitive than creatinine for detecting CIN, “future studies should prefer its use for the assessment of renal function following contrast exposure.”

Study participants had a mean age of 71 years, and 46.7% of them were

women. Of the 30 patients, 12 had nonsignificant coronary disease suitable for conservative treatment and 2 patients had multi-vessel disease requiring coronary artery bypass grafting and were referred for surgery. The remaining 16 patients underwent PCI. With regard to study limitations, the researchers pointed out that their study was conducted at a single center with a small number of patients. They noted that “it is not possible to arrive at definitive conclusions with such a small number. However, the present study is the largest to test the ultra-low contrast volume technique and the only one that included real-life consecutive patients.”

Key features of the ultra-low contrast technique, the authors noted, include the use of small catheters without sideholes and limiting contrast volume to 2 mL per injection. n

32 Renal & Urology News

MARCH /APRIL 2018 www.renalandurologynews.com

Practice Management I

n a 2014 survey, 54% of physician respondents reported experiencing at least 1 sign of burnout, up from 45.5% in 2011, according to a study published in Mayo Clinic Proceedings (2015;90:1600-1613). Satisfaction with work-life balance declined during the same period (48.5% vs 40.9%).

Electronic medical records (EMRs) may be a contributing factor, as Susan T. Hingle, MD, Chair of the Board of Regents at the American College of Physician (ACP), related. “When I would handwrite or dictate [notes], I would put them together in the context of a patient as a person, and how it is all interrelated,” said Dr Hingle, a professor in the Department of Internal Medicine at Southern Illinois University School of Medicine in Springfield. “This is missing in the current structure of most EMRs.” EMRs have also reduced the amount of time physicians can focus on the patient. Instead, many doctors end up staring at a computer screen during a visit. “Opportunities to connect and find meaning in our work is not happening because of the distractions of the task at hand,” Dr Hingle said.

To address the problem, the ACP developed the Patients Before Paper­ work initiative “to reinvigorate the

paper charts in her practice, the charts stayed at the office. Now, physicians log into email at night and see a list of prescriptions that need filling or patient questions to be answered. “I see there are 20 other things that have popped up in my inbox and I should deal with now … and if I don’t, tomorrow there will be even more,” she said.

Debra Phairas, president of Practice and Liability Consultants LLC, based in San Francisco, said she highly recommends considering the use of scribes to deal with this burnout contributor.

Having someone transcribe and enter information in EMRs while a physician treats the patient reduces the nighttime workload and allows more physician/ patient contact. Some of her clients are pain management specialists and ophthalmologists, who, because they need to have direct patient contact during visits, have used scribes for years. “I have even proven its cost-effectiveness with a family practice … so specialists can definitely afford a scribe,” she said.

Administrative tasks Increased paperwork associated with a trend toward the implementation of value-based payment systems also may contribute to physician burnout.

Physicians may be spending more time

Electronic medical records might contribute to doctor dissatisfaction because they detract from face-to-face time with patients. patient-physician relationship by challenging unnecessary practice bur­dens.”

If doctors opt to document outside of the visit, they often end up doing work at home, which eats into their personal time. In fact, Dr Hingle said physicians spend an average of 2 hours every night on documentation.

The EMR inbox The EMR inbox is another drain on physician time. When Dr Hingle used

with such tasks as medication reconciliation and other preventive care practices required to demonstrate valuebased care.

“Our ‘work intensity’ has gone up significantly,” Dr Hingle said. “Most doctors got into health care to help people, but they don’t have time to see they are doing that or reflect on the meaning of their work.”

Phairas said doctors need to delegate some of their administrative tasks. One

© VADIMGUZHVA / GETTY IMAGES

Hiring scribes, delegating tasks, and interacting socially can improve physician job satisfaction and help prevent burnout BY TAMMY WORTH

Getting together with colleagues is among the ways that can boost career satisfaction.

way to do so is by using a product like the Microsoft Outlook task function.

The task feature allows doctors to create a task, assign it to someone, and set target dates and priorities. The task will stay on the task bar. Upon completion, the person assigned to the task notifies the physicians that the task has been completed.

“If you don’t use these kinds of tools, you never know if something is being done or where it stands,” she said. “If doctors used more organizational tools, they wouldn’t be so stressed out.”

Putting policies and procedures in place for administrative tasks will help reduce the clerical work a physician does, freeing up much-needed time, she said.

Medication reconciliation Medication reconciliation, for instance, should be done ahead of time so a doctor can review the medications, make changes during a patient visit, and then give it to a medical assistant to update in an EMR. Lab tests and X-ray results can also be streamlined, Dr Hingle said. Doctors should be able to review them and either send a note for the nurse to order additional tests or sign off on them. When they do that, someone can be responsible for sending a “normal” lab letter to the patient. Someone can also be trained

to fill out disability paperwork so a physician just has to sign off on it when completed.

Making time for others It is easy to gobble down a quick lunch every day, or work in the evening after the kids go to bed, and think time is being spent wisely. Dr Hingle stresses the importance of purposefully scheduling time to connect with friends and coworkers. “I went to lunch with a colleague last week, and it was so nice to connect on that personal level,” she said. “I can’t remember the last time I did that.”

During grand rounds, her hospital once planned a “story slam” where people shared lessons they had learned from patients. They were able to spend some time reflecting on their work and connecting as a group.

One way to make more time for these kinds of things is to avoid overcommitting to things doctors feel like they have to do, but do not want to. Phairas recommends pulling back on multiple responsibilities like hospital committees when possible. “Sometimes it’s just a matter of saying no that can take pressure off,” she said. n Tammy Worth is a freelance medical journalist based in Blue Springs, MO.