Renal & Urology News - Sept-Oct 2020 Issue

SE P T E MBE R /O C T OBE R 20 20

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VOL UME 19, IS SUE NUMBER 5

Metastasectomy Ups Survival in mRCC Benefit shown in the postcytokine therapy era

BY JODY A. CHARNOW METASTASECTOMY (MS), especially complete metastasectomy (cMS), improves survival in selected patients with metastatic renal cell carcinoma (mRCC) in the postcytokine therapy era, according to a new study.

The findings build on previous studies showing a survival advantage associated with metastasectomy in patients with mRCC in the cytokine era as well as after introduction of molecular-targeted therapy (mTT).

The new study, by Hiroki Ishihara, MD, of Tokyo Women’s Medical University

in Tokyo, Japan, and colleagues included 314 patients diagnosed with mRCC from January 2008 to December 2018.

During a median follow-up period of 25.3 months, 98 patients (31.2%) underwent at least 1 MS, with 45 and 53 patients undergoing cMS and incomplete MS (icMS), respectively, and 216 patients not undergoing MS. The patients who underwent MS had a significantly longer median overall survival (OS) than the no-MS group (121.9 vs 28.1 months), the investigators reported in Urologic Oncology. The cMS group had a significantly longer

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COMMON SITES OF METASTASIS A new study confirming the survival benefit associated with metastasectomy for metastatic renal cell carcinoma showed that the lung was the most common site of metastasis.

8.9% OTHER

4.1% PANCREAS 4.1% LIVER

45.9% LUNGS

8.9% LYMPH NODES

Source: Ishihara H, Takagi T, Kondo T, Fukuda H, et al. Prognostic impact of metastasectomy in renal cell carcinoma in the postcytokine therapy era. Published online August 28, 2020. Urol Oncol.

13.7% ADRENAL GLANDS

median overall survival (median not reached [NR]) than those who underwent icMS (81.5 months) and the no-MS group (28.1 months), the investigators reported in Urologic Oncology. The OS difference between the icMS and no-MS groups was statistically significant.

Upfront Combo Superior for aRCC Dementia Risk NIVOLUMAB COMBINED with trial in which investigators led by Toni Found to Vary cabozantinib is associated with superior K. Choueiri, MD, director of the Lank oncologic outcomes and overall survival Center for Genitourinary Oncology

by ADT Type (OS) compared with sunitinib mono- at Dana-Farber Cancer Institute therapy for the first-line treatment of advanced renal cell carcinoma (aRCC), according to data presented at the European Society for Medical Oncology (ESMO) Virtual Congress 2020.

The data are the first results from the randomized phase 3 CheckMate 9ER

PFS is significantly longer with nivolumab plus cabozantinib than sunitinib alone.

in Boston, randomly assigned 651 patients with clear cell aRCC to receive nivolumab plus cabozantinib (323 patients) or sunitinib (328 patients). The primary endpoint was progression-free survival (PFS); secondary endpoints included OS and objective response rate (ORR). PFS and ORR were determined by independent central review.

Dr Choueiri’s team noted that both nivolumab, a checkpoint inhibitor, and cabozantinib, a tyrosine kinase inhibitor, have shown efficacy and a manageable safety profile in the treatment of continued on page 9

DEMENTIA RISK associated with androgen deprivation therapy (ADT) for prostate cancer (PCa) depends on the type of ADT, according to investigators.

In a study of 23,651 men with newly diagnosis PCa, investigators in Taiwan found that use of oral antiandrogen monotherapy was significantly associated with a 34% and 52% increased risk for all-cause dementia and Alzheimer disease (AD), respectively, compared with not receiving ADT in adjusted analyses, a team led by Lai-Chu See, PhD, of the Chang Gung University College of Medicine in Taoyuan, Taiwan, reported in JAMA Network Open. The investigators found no significant difference in all-cause dementia or AD risk associated with gonadotropin-releasing hormone (GnRH) agonist use or orchiectomy compared with no ADT use.

The investigators used linked data from the Taiwan National Cancer Registry, National Health Insurance Research Database (NHIRD), and the continued on page 9

14.4% BRAIN

The investigators also classified patients based on when they were diagnosed with mRCC: early mTT era (January 2008 to December 2011); late mTT era (January 2012 to August 2016); and immune checkpoint inhibitor (ICI) era continued on page 9

IN THIS ISSUE 8

ADT may enable delay of prostate cancer EBRT

11

PHPT screening of kidney stone formers found to be inadequate

11

RCC tumor growth rate depends on histologic subtype

13

Immunotherapy ups survival in patients with brain metastases

18

Prostate cancer care rebounding as COVID-19 pandemic rages on

24

Prognosis remains poor for patients with high-risk MIUC

26

Darolutamide improves survival among men with nmCRPC Most kidney stone patients go unscreened for PHPT, a study found.

PAGE 11

www.renalandurologynews.com SEPTEMBER/OCTOBER 2020

Renal & Urology News 5

FROM THE MEDICAL DIRECTOR EDITORIAL ADVISORY BOARD Medical Director, Urology

Medical Director, Nephrology

Robert G. Uzzo, MD, MBA, 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, PhD, MPH Professor & Chief, Division of Nephrology, Hypertension & Kidney Transplantation UC Irvine School of Medicine Orange, CA

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

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

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

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

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

Stanton Honig, MD Department of Urology Yale University School of Medicine New Haven, CT J. Stephen Jones, MD Chief Executive Officer Inova Health System Falls Church, VA Professor and Horvitz/Miller Distinguished Chair in Urologic Oncology (ret.)

Cleveland Clinic Lerner College of Medicine Cleveland Jaime Landman, MD Professor of Urology and Radiology Chairman, Department of Urology UC Irvine School of Medicine Orange, CA 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 Kenneth Pace, MD, MSc Assistant Professor, Division of Urology St. Michael’s Hospital University of Toronto Vancouver, Canada

Edgar V. Lerma, MD 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. Denver Rulan Parekh, MD, MS Associate Professor of Pediatrics and Medicine University of Toronto Robert Provenzano, MD Associate Professor of Medicine Wayne State University School of Medicine Detroit Vice President of Medical Affairs, DaVita Healthcare Denver Robert S. Rigolosi, MD Director, Regional Hemodialysis Center Holy Name Hospital Teaneck, NJ

Renal & Urology News Staff

Editor Jody A. Charnow

Web editor Natasha Persaud

Production editor Kim Daigneau Group creative director Jennifer Dvoretz Production manager Brian Wask

Vice president, sales operations and production Louise Morrin Boyle

Director of audience insights Paul Silver National accounts manager William Canning Editorial director, Haymarket Oncology Lauren Burke

Vice president, content, medical communications Kathleen Walsh Tulley

General manager, medical communications James Burke, RPh President, medical communications Michael Graziani Chairman & CEO, Haymarket Media Inc. Lee Maniscalco

Renal & Urology News (ISSN 1550-9478) Volume 19, Number 5. 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). For reprint/licensing requests, contact Customer Service at custserv@haymarketmedia.com. 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 © 2020.

Zoom Medicine: An Apt Metaphor in 2020

T

he practice of medicine is to the life sciences what finance and economics are to the mathematical disciplines. Both are wedged between STEM subjects and the humanities requiring skills emanating from both the right and left brain.

Read any student’s application to medical school or residency program as they explain why medicine’s intersection of science and humanity is most appealing to them. They quote our medical luminaries including Hippocrates (“Wherever the art of medicine is loved, there is a love of humanity”) and William Osler (“To serve the art of medicine as it should be served, one must love his fellow man”) who ground us in the need to balance our science with a strong human bond.

Over the past decades, multiple forces have threatened to erode the doctor-patient relationship and its foundational basis — trust. From the healthcare perspective these forces include the “corporatization” of medicine that monitors physicians’ “relative value units,” compresses visit times, and incentivizes “more” care, thereby commoditizing physicians. From the patient perspective these forces include cumbersome medical and insurance bureaucracies, inefficient processes, and systems of care that limit “face time” with their doctor.

For better or worse, the COVID-19 pandemic ushered in an era of telemedicine rapidly, stressing the doctor-patient relationship even further, particularly for the elderly and disadvantaged.

While technology is often a force multiplier for progress, it also has the potential to complicate and dehumanize the essential aspects of a physician-patient relationship. A virtual visit today is not only challenged by time constraints but also by imperfect technology. Delivering the news of adverse test results or counseling on an escalating care plan with significant risks (eg, surgery or chemotherapy), all while battling connectivity where you cannot read each other’s body language or provide reassurance, diminishes understanding, trust, commitment, and even outcomes.

Psychologists say that the art of the touch is essential to healing. The tradeoff for the logistical benefits of telemedicine is a diminished personal connection. In some cases, the benefits predominate. In others, “Zoom Medicine” is just another force that widens the relationship gap between doctor and patient.

As telehealth evolves, we must not only focus on how it allows “more” care but rather take a holistic view and work to integrate technology to improve care, compliance, and trust. This may sometimes mean less virtual “face time” and more actual “face to face” time.

Robert G. Uzzo, MD, MBA, FACS G. Willing “Wing” Pepper Chair in Cancer Research Professor and Chairman, Department of Surgery Fox Chase Cancer Center, Temple University 1. Ha JF, Longnecker N. Doctor-patient communication: a review. Ochsner J. 2010;10(1):38-43.

6 Renal & Urology News

SEPTEMBER/ OCTOBER 2020

www.renalandurologynews.com

Contents

SEPTEMBER/OCTOBER 2020

Urology 11

ONLINE

this month at renalandurologynews.com

11

13

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

26

HIPAA Compliance Read timely articles on various issues related to keeping protected health information secure.

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

Immunotherapy Improves Survival of Patients With Brain Metastases Immunotherapy improves overall survival of cancer patients with brain metastases who underwent definitive surgery for the primary tumor, a study found.

Darolutamide for nmCRPC Prolongs OS In the final analysis of the phase 3 ARAMIS trial, darolutamide therapy was associated with a 31% lower risk for death compared with placebo.

11

PHPT Testing Low in Kidney Stone Formers New findings suggest clinicians are missing an opportunity to prevent recurrent stones.

25

Hyponatremia Occurs Often in COVID-19 Of 4645 patients admitted to New York City hospitals with COVID-19, hyponatremia at admission was present in 1373 (30%) cases, a study found.

25

New Index Useful As Muscle Mass Marker in HD Patients A simplified creatinine index that reflects the creatinine generation rate of an individual hemodialysis patient is reliable and can predict survival.

News Coverage Visit our website for daily reports on the latest developments in clinical research.

Renal Cell Carcinoma Subtype Impacts Tumor Growth Rate Clear cell RCC tumors grow faster than those of papillary histology, new data show.

VOLUME 19, ISSUE NUMBER 5

CALENDAR Editor’s note: With the cancellation of medical conferences thus far in 2020 in response to the COVID-19 pandemic and the status of other meetings unclear, we are providing listings of medical conferences scheduled for 2021.

Genitourinary Cancer Symposium San Francisco January 21 to 23, 2021 American Urological Association Annual Meeting Las Vegas May 13–14, 2021 ERA-EDTA Annual Congress Berlin, Germany June 5–8, 2021 Canadian Urological Association Annual Meeting Niagara Falls, Ontario, Canada June 26–29, 2021 International Continence Society Annual Meeting Melbourne, Australia October 12–15, 2021

Nephrology

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

URS Suitable for Selected UTUC Cases Ureteroscopic management may be an alternative to radical nephroureterectomy, according to researchers.

■

26

CVD Deaths Declining in Young Dialysis Patients Compared with children starting dialysis in 1995, those starting after 2006 had a 26% decreased risk for cardiovascular-related deaths in adjusted analyses.

Monitoring SCI may be used as physical activity

indicator to guide and coach dialysis patients in order to trigger physical activity.

See our story on page 25

28

Departments 5

From the Medical Director Zoom Medicine: An Apt Metaphor in 2020

8

News in Brief Anemia may increase the risk of progression to ESKD

27

Ethical Issues in Medicine COVID-19 presents physicians with a prescribing dilemma

28

Practice Management How to use psychology to improve debt collection

8 Renal & Urology News

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News in Brief

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

Short Takes Anemia May Raise Risk of Progression to ESKD

patients diagnosed with gout and

Anemia may increase the risk of pro-

69,326 matched control participants

gression to end-stage kidney disease

in Taiwan, gout patients receiving ULT

(ESKD), new study findings published

with febuxostat, allopurinol, colchicine,

in Kidney360 suggest.

sulfinpyrazone, and benzbromarone

In a study that included 69,326

Among 3919 patients with mild-to-

had a significant 96%, 43%, 28%, 43%,

moderate CKD in the Chronic Renal In-

and 11% decreased risk for type 2

sufficiency Cohort (CRIC) study, 1859

diabetes, respectively, compared with

(47%) had anemia at baseline. ESKD

gout patients not receiving ULT, Yi-Jen

developed in 1010 patients (25.7%)

Fang, of Kaohsiung Medical University,

over a median follow-up of 7.8 years.

­Kaohsiung, Taiwan, and colleagues

In multivariable analyses, patients

reported.

with anemia had a significant 1.6-fold those without anemia, Santosh L.

FDA Cites Deficiencies in Veverimer NDA

Saraf, MD, of the University of Illinois

The US Food and Drug Administration

at Chicago, and colleagues reported.

(FDA) has issued a Complete Response

In stratified analyses, anemia was

Letter (CRL) to Tricida regarding its

associated with a significant 2-fold

New Drug Application for veverimer for

higher risk for ESKD in men, but was

the treatment of metabolic acidosis in

not significantly associated with ESKD

patients with chronic kidney disease.

higher risk for ESKD compared with

in women.

In the CRL, the FDA identified deficiencies in the application and requested

Urate-Lowering Therapy Reduces Diabetes Risk

“additional data beyond the TRCA-

Urate-lowering therapy (ULT) for

the magnitude and durability of the

gout may lower the risk for type 2

treatment effect of veverimer on the

diabetes, according to research find-

surrogate marker of serum bicarbonate

ings published in BioMed Research

and the applicability of the treatment

International.

effect to the US population.”

301 and TRCA-301E trials regarding

COVID-19 and Telemedicine According to experimental estimates by the National Center for Health Statistics based on surveys conducted between June 9 and July 6, 2020, 36.6% of adults in the United States said they had a provider who offered telephone or video appointments during the previous 2 months compared with 14.1% before the COVID-19 pandemic. The proportions varied by age group.

■ During pandemic

50

45.9% 39.8%

PERCENTAGE

40 30 20

■ Before pandemic

30.2%

13.7%

13.9%

15.4%

10 0

18–44

45–64 AGE (YEARS)

Source: National Center for Health Statistics. Centers for Disease Control and Prevention.

65 and older

Delaying EBRT for Prostate Cancer Possible With ADT D

elaying initiation of external beam radiation therapy (EBRT) for localized prostate cancer (PCa) for up to 6 months by using androgen deprivation (ADT) is not associated with worse survival compared with initiating EBRT before ADT, according to investigators.

In a study of 63,858 men, the 10-year overall survival (OS) rates for men with unfavorable intermediate-risk PCa who initiated EBRT 0 to 60 days before starting ADT and 1 to 60, 61 to 120, and 121 to 180 days after starting ADT were 59.2%, 57.9%, 62.3%, and 58.9%, respectively, in adjusted analyses, Vinayak Muralidhar, MD, MSc, of Brigham and Women’s Hospital in Boston, and colleagues reported in JAMA Oncology. Among men with high-risk or very high-risk PCa, the 10-year OS rates were 58.9%, 51.7%, 54.8%, and 52.4%, respectively. The authors noted that “if COVID-19 outbreaks continue to occur sporadically during the coming months to years, these data could allow future flexibility about the timing of RT initiation.”

Study: Proteinuria Reduction in FSGS Reduces ESKD Risk U

rine protein reduction in patients with focal segmental glomerulosclerosis (FSGS) is associated with improvement in kidney function and a reduced risk for end-stage kidney disease (ESKD), new data suggest.

In an analysis of 138 patients with steroid-resistant primary FSGS who participated in a multicenter randomized trial comparing treatment with cyclosporine and mycophenolate mofetil, investigators found that changes in proteinuria over 26 weeks were significantly related to estimated glomerular filtration rate (eGFR) slope. Each 1-unit decrease in log-transformed urinary protein-creatinine ratio (UPCR) was associated with a 3.90 mL per year rise in eGFR. In addition, each 1-unit reduction in log-transformed UPCR was significantly associated with a 77% decreased risk for ESKD, Jonathan P. Troost, PhD, of the University of Michigan in Ann Arbor, and colleagues reported in the American Journal of Kidney Diseases.

NAC for High-Grade UTUC Found to Improve Outcomes N

eoadjuvant chemotherapy (NAC) for patients undergoing nephroureterectomy for high-grade clinically non-organ confined upper tract urothelial carcinoma (UTUC) is associated with higher rates of pathologic downstaging and improved overall survival, investigators reported in Urology.

A team led by Douglas S. Scherr, MD, of New York-Presbyterian Hospital, Weill Cornell Medicine, in New York, studied 10,315 chemo-eligible UTUC patients identified using the National Cancer Data Base. Of these, 296 (2.9%) received NAC prior to nephroureterectomy. Among patients with clinically non-organ confined disease, 27.1% of those who received preoperative NAC had organ confined disease at the time of surgery compared with 1.4% of those who had surgery as initial therapy. For the overall cohort, NAC was significantly associated with an approximately 20% decreased risk of death compared with no NAC. NAC was not significantly associated with a survival advantage among patients with organ confined disease.

www.renalandurologynews.com SEPTEMBER/OCTOBER 2020

Combo superior for aRCC continued from page 1

aRCC. Cabozantinib, they explained, has immunomodulatory properties that may counteract tumor-induced immunosuppression, thus provide a rationale for using the both drugs in combination.

Study participants had a median follow-up of 18.1 months (minimum 10.6 months). Compared with sunitinib monotherapy, nivolumab plus cabozantinib treatment was significantly associated with a 49% decreased risk of progression, with a median time to progression of 16.6 months for the combination therapy arm compared with 8.3 months in the sunitinib arm.

The combination treatment was significantly associated with a 40% decreased risk of death compared with sunitinib monotherapy, with median survival times not reached. Results were consistent across prespecified International Metastatic RCC Database Consortium (IMDC) risk and PD-L1 subgroups.

The ORR was significantly higher in the combination arm than among sunitinib recipients (55.7% vs 27.1%). A significantly higher proportion of patients

Metastasectomy survival continued from page 1

(September 2016 to December 2018).

In the MS-treated patients, OS was comparable throughout early mTT, late mTT, and ICI eras (median 121.9 months vs NR vs NR), Dr Ishihara and colleagues reported.

The most frequent organ sites treated with MS were the lungs (45.9%), followed by the brain (14.4%), adrenal glands (13.7%), lymph nodes (8.9%), and liver and pancreas (4.1% each), according to the investigators.

“This retrospective study using realworld data showed that MS significantly

Dementia risk continued from page 1

Taiwan National Death Registry. Their analysis included the following ADTs: the oral antiandrogens bicalutamide, flutamide, and cyproterone; the GnRH agonists leuprolide, goserelin, triptorelin, and buserelin; and bilateral orchiectomy.

Of the 23,651 men, 11,817 (50%) received GnRH agonists, 4054 (17.1%) received antiandrogen monotherapy, 876 (3.7%) underwent orchiectomy, and 6904 (29.2%) did not receive ADT. A total of 1525 men were diag-

in the combination than monotherapy arm achieved a complete response (8.0% vs 4.6%).

In addition, the median duration of response was significantly longer for the nivolumab-cabozantinib than sunitinib arm (20.2 vs 11.5 months).

Dr Choueiri and his colleagues concluded that the safety profile of the combination therapy was manageable and consistent with the adverse event (AE) profiles of nivolumab and cabozantinib use as single agents.

Grade 3 or higher treatment-related AEs (TRAEs) occurred in 60.6% of the combination arm compared with 50.9% of the sunitinib arm.

Discontinuation of study drugs because of TRAEs occurred in 3.1% of patients in the combination arm and 8.8% of those in the sunitinib arm.

In an ESMO press release, Dominik Berthold, MD, Head, Specialised Consultation for Urological Cancers Medical Oncology Service, Department of Oncology, Lausanne University Hospital, Switzerland said: “CheckMate 9ER met its efficacy endpoints and the combination can be considered a new first-line treatment option.” ■

improved OS of mRCC in the postcytokine therapy era,” the authors wrote.

“This prognostic impact was remarkable in the cMS [group], but even icMS had a therapeutic effect compared to nonMS.” The investigators said their study, as far as they are aware, is the first to examine the effect of MS with regard to its completeness and eras of systemic

Survival benefit most pronounced with complete metastasectomy. nosed with incident dementia during a median follow-up period of 3.46 years.

In a discussion of study limitations, the authors noted that dementia or AD events recorded using diagnostic codes in the claims data may be inaccurate. “However, we examined patient records from more than 2 clinic visits by specialists rather than general practitioners to increase diagnostic validity,” they wrote.

In addition, as the study was observational and the NHIRD has inherent limitations, they could not account for residual confounding from unmeasured variables, such as smoking status,

Renal & Urology News 9

Multiparametric MRI Can Confirm MIBC Diagnosis MULTIPARAMETRIC magnetic reso-

concluded. “This will decrease time

nance imaging (mpMRI) can differenti-

between diagnosis and definitive treat-

ate between nonmuscle-invasive and

ment,” they wrote. “Furthermore, this

muscle-invasive bladder cancer with

will reduce the risk of tumor-spill by

a high degree of accuracy, accord-

bladder perforation after TUR-BT.”

ing to a new systematic review and meta-analysis.

Based on the finding, investigators

In an analysis of data from 20 studies that included 1724 patients with 1778 lesions, Cornelissen’s team

recommend using mpMRI for diag-

found that the pooled sensitivity and

nostic confirmation when stage T2 or

specificity for differentiating stages

higher tumors are suspected at the

T1 or less from T2 or higher tumors

time of first tumor detection, accord-

were 92% and 88%, respectively. The

ing to a report published in Urology.

sensitivity and specificity for differen-

When the tumor is confirmed

tiating stage T2 or less tumors from

as stage T2 or higher, treatment

stage T3 or higher tumors were 71%

could be started immediately

and 77%, respectively. The sensitivity

rather than performing transure-

and specificity, respectively, were 75%

thral resection of bladder tumor

and 95% for stage T1, 62% and 66%

(TUR-BT), Suzan Cornelissen, MSc,

for stage T2, 59% and 80% for stage

of Radboud University in Nijmegen,

T3, and 77% and 97% for stage T4,

The Netherlands, and her colleagues

according to the investigators. ■

therapy, including the recent ICI era.

“These data add to a growing body of literature suggesting that metastasectomy may continue to play a role in the care of appropriately selected patients with metastatic renal cell carcinoma despite the availability of increasingly effective systemic therapies,” said Timothy D. Lyon, MD, of Mayo Clinic in Jacksonville, Florida, who has studied the impact of MS on survival among patients with mRCC but was not involved in the new study.

As the study was not randomized, Dr Lyon pointed out, “the observed difference in survival could be due to selection bias whereby those with more

favorable tumor biology were chosen for metastasectomy, and thus we can’t be completely sure the survival advantage was attributable to the metastasectomy itself.”

Available data on the efficacy of metastasectomy in the immunotherapy era, either alone or in combination with targeted agents, are still quite limited.

In the current study, he noted, only 18 patients underwent MS during this time period.

“We hope several ongoing placebocontrolled trials examining adjuvant immunotherapy following nephrectomy or metastasectomy will shed some light on this issue,” he said. ■

family history, physical inactivity, and education level.

Dr See and colleagues noted that the underlying mechanism by which ADT causes dementia is unclear and could be multifactorial. They cited epidemiologic and in vivo studies suggesting that luteinizing hormone (LH) contributes to cognitive decline and beta-amyloid accumulation, a pathologic hallmark of AD. GnRH agonists reduce testosterone and LH levels, they explained, and their study found no clinically meaningful effect of these medications on dementia or AD risk compared with no ADT use.

“We speculated that increased LH level on treatment using antiandrogen monotherapy could partly explain the association of antiandrogen monotherapy with dementia and AD,” they wrote.

The new findings differ from those of a previous study of 30,903 men with newly diagnosed nonmetastatic PCa in the United Kingdom. The study, which was published in the Journal of Clinical Oncology in 2017, found no significant increase in dementia or AD risk associated with GnRH agonists alone, oral antiandrogens alone, GnRH agonists plus oral antiandrogens, and other types or combinations of ADT. ■

www.renalandurologynews.com SEPTEMBER/OCTOBER 2020

Renal & Urology News 11

PHPT Testing Low in Kidney Stone Formers Many patients do not receive guideline-concordant screening for primary hyperparathyroidism

URS Suitable For Selected UTUC Cases URETEROSCOPIC management of selected upper tract urothelial carcinoma (UTUC) cases can be an alternative to the gold standard radical nephroureterectomy (RNU), according to a new study.

The findings were based on 168 patients who underwent retrograde ureteroscopy (URS) as the primary treatment for lowgrade UTUC. A team led by Demetrius H. Bagley, MD, of Thomas Jefferson University Hospital in Philadelphia, found a 5-year cancer-specific survival rate of 92.6% and 5-year overall survival rate of 80.9%. Recurrence-free survival was 30%, with an average tumor size on recurrence of 6.39 mm. The progression-free survival rate was 75%, with a renal preservation rate of 71.4%.

“The use of URS in the treatment of UTUC is associated with long-term patient viability,” the authors concluded in a report published in Urologic Oncology. “URS resulted in a high rate of recurrence but led to renal preservation in 71.4% of patients followed over 5 years. This suggests that URS is an

Veterans with an estimated glomerular filtration rate (eGFR) of less than 60 mL/min/1.73 m2 were also less likely to undergo screening. According to the investigators, patients with an eGFR less than 45 mL/min/1.73 m 2 and hypercalcemia should be screened for PHPT because hypercalcemia may be associated with hypertension and progression of chronic kidney disease.

“The low prevalence of PTH testing in veterans with kidney stones and hypercalcemia suggests that clinicians are missing an opportunity to prevent recurrent kidney stones by diagnosing and treating PHPT despite guidelines by the American Urological Association and European Association of Urology that recommend PTH testing,” Dr Ganesan’s team stated.

Patients with serum calcium levels exceeding 10.5 mg/dL in 1 or multiple tests were significantly more likely to undergo serum PTH testing by 7% and 8%, respectively. In addition, patients

acceptable option for long-term management of low grade UTUC.” The patient population had a median age of 69.8 years and mean follow-up time of 5.53 years. The maximum follow-up time was 23 years. Of the 168 patients, 107 (66%) were male and 157 (93.4%) were White. The average tumor size on initial excision was 16.8 mm.

“To our knowledge, this cohort represents the largest patient population and length of follow up to date, making our study ideal to make stronger inferences about this rare disease and helping guide treatment,” the authors stated.

Dr Bagley and his colleagues noted that up to 80% of patients with low-risk UTUC continue to undergo RNU even though urology association guidelines endorse the use of kidney-sparing techniques for these patients.

“More must be done to educate urologists on the benefits of renal-sparing procedures for low risk UTUC,” the authors wrote. “In the absence of prospective studies, long-term data add to the knowledge base pointing to the safety and efficacy of URS in the patient population.”

The investigators acknowledged that their study had limitations. For example, the retrospective design could increase the risk of bias, and the small sample size limited their ability to detect statistically significant effects. ■

A new study reveals a low prevalence of PTH testing in veterans with kidney stones.

receiving specialty care from either a nephrologist or a urologist or both had a 1.6- and 6.6-fold higher likelihood of PHPT screening, respectively, compared with patients seeing neither of these specialists. Patients receiving care from an endocrinologist had a 4.9-fold higher likelihood of screening.

Of the 717 patients with biochemical evidence of PHPT, 189 (26.4%) underwent parathyroidectomy within 2 years of a stone diagnosis, even though parathyroidectomy may improve skeletal, cardiovascular, and neuropsychiatric outcomes.

“PTH testing was 2-fold to 5-fold higher among those who had appointments with specialists such as nephrologists, urologists, and endocrinologists,” Quan-Yang Duh, MD, of the Veterans Health Administration Medical Center in San Francisco, California, and colleagues highlighted in an accompanying editorial. “This specialty care also partially explains the wide variability (4%-57%) in testing rates at different VHA facilities. Perhaps these specialists were more likely to recognize the possibility of hyperparathyroidism, or perhaps the same primary care physicians who recognized this disease also tended to refer to specialists. This finding suggests how we may solve the problem of underdiagnosis.” ■

Renal Cell Carcinoma Subtype Impacts Tumor Growth Rate GROWTH RATES of renal cell carci-

Clear cell RCC grew faster than

noma (RCC) tumors differ by histologic

papillary type 1 (0.25 vs 0.02 cm/yr on

subtypes, according to a new study.

average), Dr Finelli’s team reported in

Antonio Finelli, MD, of Princess

European Urology. Overall, 60 lesions

Margaret Cancer Centre and the

progressed: 49 (82%) by rapid growth

University Health Network, University

(volume doubling), 7 (12%) increased

of Toronto, and his colleagues ana-

to 4 cm or more, and 4 (6.7%) by both

lyzed 136 biopsy-proven RCC tumors

criteria. Metastases developed in 6

in 134 patients managed with active

patients, all of whom had clear cell RCC.

surveillance (AS). Their objective was to

The predicted growth rates by diam-

compare growth rates and progression

eter and volume for clear cell RCC over

of different histologic subtypes of small

3 years were 0.28 cm/yr and 2.4 cm3/

RCC tumors. The investigators defined

yr, respectively. Over the same period,

tumor progression as a sustained size

the average diameter- and volume-

of 4 cm or greater or volume doubling

predicted growth rates of papillary

in 1 year. Patients underwent serial

type 1 tumors remained essentially

imaging with computed tomography,

unchanged (0.017 cm/yr and –0.006

magnetic resonance imaging, or ultra-

cm3/yr), the researchers reported.

sonography at 3, 6, and 12 months and annually thereafter.

At the time of their first tumor image,

In the absence of validated prognostic markers in patients with small renal masses managed by AS, the authors

patients had a median age of 70 years

explained, better understanding of

and a median tumor diameter of 2.3 cm.

biopsy-characterized RCC tumor kinet-

The median follow-up time for patients

ics may enable improved individualized

who remained on AS was 5.8 years.

treatment recommendations. ■

© DR_MICROBE / GETTY IMAGES

ALTHOUGH 3% TO 5% of patients with kidney stones have primary hyperparathyroidism (PHPT), a treatable cause of recurrent stones, only 1 in 4 stone formers with hypercalcemia undergo testing for PHPT, new study findings suggest.

In a study of 7561 patients with kidney stones and hypercalcemia (mean age 64.3 years; 94.4% male; 75.0% White) from a Veterans Health Administration (VHA) database, only 24.8% had their serum parathyroid hormone (PTH) level measured, Calyani Ganesan, MD, MS, of the Stanford University School of Medicine in Palo Alto, California, and colleagues reported in JAMA Surgery. PTH testing rates across the 130 VHA facilities ranged from 4% to 57%. Patients residing in the Southeastern United States were the least likely to be screened for PHPT. This cohort comprised mostly men, but PHPT is more likely to develop in women, the study authors noted.

www.renalandurologynews.com SEPTEMBER/OCTOBER 2020

Immunotherapy Improves Survival of Patients With Brain Metastases Immunotherapy Offers Survival Edge

25

22.6

20

for predicting lupus nephritis (LN), investigators in China reported. comparing with 212 patients with

10.09

10

(PDW) may be useful as a marker

The finding emerged from a study

20.53 15.08

15

Low PDW May Predict Lupus Nephritis PLATELET DISTRIBUTION width

Immunotherapy is associated with longer overall survival among patients with brain metastases, particularly those who receive immunotherapy in addition to radiation therapy (RT), a study found.

MONTHS

IMMUNOTHER APY improves overall survival (OS) of patients with brain metastases (BMs) who underwent definitive surgery for the primary tumor, according to investigators.

In a study of 3112 patients with BMs from kidney cancer, non-small-cell lung cancer, breast cancer, colorectal cancer, and melanoma, immunotherapy was significantly associated with a 38% decreased risk of death compared with no immunotherapy in adjusted analyses, Saber Amin, MD, PhD, of the University of Nebraska Medical Center in Omaha, and colleagues reported in JAMA Network Open. RT plus immunotherapy was significantly associated with a 41% decreased risk of death compared with RT alone.

“What is unique in our study is that we found that immunotherapy was associated with significantly improved survival in patients with BMs who received surgery of the primary site, which has not, to our knowledge, been investigated so far,” Dr Amin and coauthors wrote.

Immunotherapy improved median OS by 7.5 months regardless of what other treatments patients received, according to the investigators. RT plus immunotherapy improved median OS by 10.4 months compared with RT alone.

Renal & Urology News 13

systemic lupus erythematosus (SLE) and 201 healthy controls.

The level of PDW was decreased

5

significantly in the SLE group, and Immunotherapy

No Immunotherapy

RT + Immunotherapy

RT alone

Source: Amin S, et al. Association of immunotherapy with survival among patients with brain metastases whose cancer was managed with definitive surgery of the primary tumor. JAMA Netw Open. 2020;3(9):e2015444. Published online ahead of print.

The researchers found no association between chemotherapy plus immunotherapy or chemoradiation plus immunotherapy with improved OS. The improved OS in patients who received RT plus immunotherapy may be associated with the abscopal effect of RT, according to the investigators. “After a tumor is irradiated,” the authors explained, “injury in the tumor may lead to the release of tumor-associated antigens, which can stimulate a tumor-specific immune response, allowing the immune cells (ie, T-cells) to recognize and attack

both the primary tumor and metastatic disease in a sort of autovaccination. Immunotherapy may enhance the optimal effect of the abscopal effect by increasing and improving the immune response to tumor-associated antigens, notably when the removal of the primary tumor minimizes tumor burden.”

The investigators identified study patients using the National Cancer Database. Of the 3112 patients, 1436 (46.1%) were men, 2714 (87.8%) were White, 257 (8.3%) were Black, and 123 (4%) belonged to other racial and ethnic groups. ■

was negatively correlated with SLE disease activity 2000 (SLEDAI-2K) score, Haitao Yu of The First Hospital of Lanzhou University in China and colleagues reported in International Immunopharmacology.

The investigators classified patients with SLE into 3 groups based on whether they had a low, normal, or high PDW. They defined low PDW as less than 15%, normal PDW as 15% to 17%, and high PDW as more than 17%. The low-, normal-, and high-PDW groups included 132 (62.3%), 42 (19.8%), and 38 (17.9%) patients, respectively.

Of the 212 patients with SLE, 75 (35.4%) had LN. Compared with the normal- and high-PDW groups, the low-PDW group had significantly more LN cases (55% vs 14% and 6%,

De Novo Metastatic PCa Has a Better Prognosis

respectively).

MEN WHO HAVE metastatic prostate cancer (PCa) at initial presentation are less likely to die from the malignancy compared with men who progress to metastatic PCa after initial therapy, according to a new study.

The finding suggests that “these entities may have distinct biology informed by prior treatment exposure,” Hala T. Borno, MD, of the University of California, San Francisco, and collaborators concluded in a report published in Urologic Oncology.

The study examined data from 14,753 patients in the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) registry diagnosed with PCa from 1990 to 2016. Of these, 669 (5%) had metastatic disease: 303 (45%) at diagnosis (de novo metastatic PCa) and 366 (55%) who progressed to metastatic disease after initial therapy (recurrent metastatic PCa). The median follow-up time was 40 months

clinical cutoff value for PDW was 12.9,

for men with de novo metastatic PCa compared with 22 months for those with recurrent metastatic PCa. Among the patients with metastatic disease at diagnosis, 31 (10%) received initial local therapy and 272 (90%) received initial hormonal therapy. Among patients who progressed to metastatic disease, 239 (65%) received initial local therapy and 127 (35%) received initial systematic hormonal therapy.

After adjusting for sociodemographic factors, diagnosis year, comorbidities, and marital status, patients with metastatic disease at diagnosis had a significant 34% lower risk of cancer-specific mortality than those who progressed to metastatic disease, the researchers reported. They found no difference in the stratified analysis between men who received combined local and hormonal therapy compared with local therapy alone.

“These data support the notion that local management may not confer a

survival benefit in an unselected population of patients with metastatic disease,” the authors wrote.

Dr Borno and colleagues concluded that their data “contribute to the growing literature characterizing the role of local therapy as part of an evolving treatment landscape for advanced disease.”

The investigators acknowledged that their study, which is based on data from a longitudinal observational registry, has some limitations. Clinical and laboratory data reporting was decentralized, and this could have introduced error into their analyses.

“Specifically, the diagnosis of metastatic disease heavily relied on imaging reports from various radiology centers,” the authors explained. “Given that bone scans may become positive for non-malignancy associated causes, this decentralization may have decreased the internal validity of the study ­outcomes.” ■

A receiver operating characteristic curve analysis found that the optimal which had 87.4% sensitivity and 74.6% specificity for distinguishing LN from SLE and other types of organ damage, according to Dr Yu’s team.

The study also found that the lowPDW group had significantly higher 24-hour urine protein levels than the normal- and high-PDW groups (0.74 vs 0.40 vs 0.22 g/24 h, respectively).

The authors concluded that a low PDW together with high 24-hour urine protein level may provide a strategy to diagnose LN. The investigators acknowledged that a limitation of their study was that it was conducted at a single center, which raises the possibility of bias. They also did not investigate the mechanism underlying involvement of PDW in SLE. ■

18 Renal & Urology News

SEPTEMBER/OCTOBER 2020 www.renalandurologynews.com

n FEATURE

Prostate Cancer Care Picks Up As Pandemic Rages On Caseloads dropped sharply early in the COVID-19 crisis but appear to be rebounding

R

outine and nonessential healthcare services came to a nearly complete halt in many places throughout the United States as a result of the coronavirus disease 2019 (COVID-19) pandemic. Hospitals and medical practices discontinued or substantially curtailed provision of all but the most necessary procedures. Fearing infection with the novel coronavirus that causes COVID19, many patients avoided contact with the healthcare system. Caseloads dropped precipitously across physician specialties.

Physicians who manage patients with prostate cancer (PCa) have not been spared. Urologists, for example, have had to postpone performing prostate biopsies and radical prostatectomies (RPs) except in the most urgent cases. In interviews with Renal & Urology News, urologists and medical oncologists across the nation explained their PCa caseloads, which plummeted for a few months early in the pandemic, have rebounded substantially even in areas that were severely impacted by COVID-19 outbreaks.

New York City Those hard-hit places include New York City, which quickly emerged as the nation’s pandemic epicenter. As early as April 1, for example, the city’s health department reported a total of 45,707 confirmed COVID-19 cases and 1374 deaths.1 Those numbers soared to 164,505 and 13,000, respectively,

by April 30, and further swelled to 229,980 and 19,042, respectively, as of August 30.1 Patients with COVID19 overwhelmed hospitals. All but the most urgent medical procedures were postponed. Physicians with Integrated

Prostate biopsies were among the procedures that urologists across the United States had to postpone during the COVID-19 crisis.

Medical Professionals, parent company of Advanced Urology Centers of New York and Advanced Radiation Centers of New York, an independent group with headquarters in Farmingdale, New York, and a clinical affiliate of The Mount Sinai Health System in New York City, can attest to how COVID-19 hampered PCa care.

Prior to the pandemic, urologists in the group performed around 1000 prostate biopsies a quarter, said urologist Deepak A. Kapoor, MD, the group’s chairman and chief executive officer. For a few months after the pandemic struck, the number of these biopsies plunged to only a few per week, he said.

Dr Kapoor pointed out that prostate biopsies can result in sepsis, the most significant complication of the procedure, as well as bleeding and urinary retention.

Patients may require h ­ ospitalization if

these problems occur. This would mean using hospital resources when they were badly needed to care for COVID-19 patients. “As a result, we felt that it was our moral obligation to not do elective prostate biopsies,” he explained. “As a consequence, many of those biopsies were delayed.”

However, the group is now ramping up prostate biopsies, Dr Kapoor said.

He estimates that his group is at 75% to 80% of the prostate biopsy volume they had before the pandemic. A return to normal biopsy caseloads was delayed in part because patient anxiety about contracting COVID-19 kept individuals from undergoing the procedure, he said. Another factor was the availability of procedure room time; “because we still try to do biopsies transperineally, our ability to do the procedure is a little bit restricted,” Dr Kapoor related.

Dr Kapoor said his group moved quickly to establish safety protocols.

During the second week of March, the group formed a COVID-19 task force that had representatives from every specialty and service department. “We pulled together as a team in amazing collective fashion in a very short period of time to create protocols that would enable us to continue to function clinically while keeping our employees and our patients safe … and most importantly, out of the hospital.”

“Our goal during the pandemic was to keep our patients out of the hospital because if you have a trip to the hospital you’re in big trouble,” said Ann E. Anderson, MD, the group’s director of pathology. Not only would patients be at risk of contracting COVID-19, they might not have a bed or stretcher available to lie on, she said.

Dr Anderson and her pathology colleagues developed a virtual laboratory methodology whereby physicians could order laboratory tests via telemedicine.

This way, patients could go to diagnostic testing sites in their community rather than have to travel to one of the group’s offices.

The group was able to increase caseloads largely because of COVID-19 testing, Dr Anderson said. “We were extremely proactive in COVID testing during the height of the pandemic for our staff,” she said. “That was a very big boost to the staff morale and the company’s ability to provide care for the patients.”

Longer-Duration Hormonal Injections During the height of the pandemic in New York City, Dr Kapoor related, some patients with PCa who were faced with

© ANTONIA REEVE / SCIENCE SOURCE

BY JODY A. CHARNOW

www.renalandurologynews.com SEPTEMBER/OCTOBER 2020

postponement of RPs opted instead to have radiation therapy rather than delay treatment. Other patients with PCa were given androgen deprivation therapy (ADT) as a stopgap measure until they could undergo RP, Dr Kapoor said. For patients with advanced PCa, urologists gave 6-month, rather than 3-month, injections of hormonal therapy to increase the interval between patient visits. The only patients with PCa for whom care changed little during the pandemic were those with castrationresistant disease. As they are high-risk patients, “we had no choice but to bring them in on a regular basis to make sure they were adequately followed,” Dr Kapoor said.

Telehealth played a big part in cutting down on the number of face-to-face encounters with patients, he said. His group went from having no telehealth encounters on March 12 to nearly 2000 telehealth encounters a week by the end of March. “I don’t know what we would have done had we not been able to at least communicate with those patients virtually,” he said.

The expanded use of telehealth was enabled in large part by the Centers for Medicare and Medicaid Services (CMS), which issued waivers that gave greater flexibility in the use of this modality and established payment parity between telehealth and regular in-person clinical care for Medicare patients.

‘Semblance of Normalcy’ UroPartners, LLC, a large urology group practice that serves the Chicago area, experienced a 70% decline in patient visits early during the pandemic, but the situation has improved substantially, said the group’s president and chief executive officer, Richard Harris, MD, who also is president of the Large Urology Group Practice Association (LUGPA). In-office visits bounced back much faster than he expected, he said. “We’re back up to 98% of our pre-COVID numbers,” Dr Harris explained, adding that his group figured out how to work around the difficulties posed by the pandemic so they could keep everybody safe while providing care. He credits telehealth for enabling providers in his group to “stay in the loop” with many patients. “The ability to do telemedicine has had a profoundly positive impact on our ability to treat these patients,” Dr Harris said.

Dr Harris said his group’s surgicenter is handling more cases than ever because many patients do not want to undergo procedures in a hospital for fear of COVID-19. As elsewhere, RPs were put off for a couple of months, but

the number of these procedures began rising around May or June.

“I think most people are getting back up to speed as far as patient care,” said Dr Harris. “It’s not quite business as usual. I don’t know that it’s ever going to be until we have a vaccine or this [virus] has gone away. But at least we’re back to some semblance of normalcy.”

Renal & Urology News 19

Radical Prostatectomy Delay Not Tied to Worse Oncologic Outcomes

BY JODY A. CHARNOW Delayed radical prostatectomy (RP) for intermediate- and high-risk prostate cancer (PCa) does not appear to adversely affect oncologic outcomes,

Pacific Northwest

according to recent studies prompted by the COVID-19 pandemic.

PCa care also appears to be rebounding in the Washington State and the Pacific Northwest in general, according to Daniel W. Lin, MD, professor and chief of urologic oncology at the University of Washington in Seattle, where he also is director of the Institute for Prostate Cancer Research. The COVID-19 outbreak in Washington State — which had 74,320 confirmed COVID-19 cases and 1905 related deaths as of August 302 — was not as severe as in New York City, but during the height of the outbreak from mid-March to the end of April the “center basically stopped doing biopsies for routine elevated PSA,” Dr Lin explained. The same was true for most, if not all, of the Pacific Northwest.

“Patients, we think, probably were not hurt by a few-month delay,” he said.

Discontinuation of prostate biopsies for several months, however, has led to a decline in new PCa diagnoses, he noted.

There was a period of a few months when many hospitals nationwide were discouraging or postponing surgeries and radiation therapy for lower-risk PCa, not only to protect patients and staff from COVID-19 transmission, but also out of concern about running out of PPE and other resources that might be needed for life-saving COVID-19 care. At the University of Washington, some robotic RPs for low-risk PCa were postponed because of concern about using up resources.

Still, patients have been reluctant to make medical visits, and this has devastated primary care practices, according to Dr Lin. “Patients are fearful of seeing their healthcare provider. They are not seeking general medical care, and thus are not getting screened for prostate cancer.” This fact has led to a decrease in patient referrals to urologists because of elevated PSA. Even though Oregon, another Pacific Northwest state, had a relatively mild COVID-19 outbreak (with 26,554 and 458 confirmed cases and deaths as of August 303) compared with New York City and some other cities, COVID-19 altered medical care.

“We had a statewide halt on nonessential medical procedures that ended on

and high-risk PCa. Romain Diamand, MD, of Université Libre de Bruxelles,

In a study of 926 men undergoing RP across Europe for intermediateBrussels, Belgium, and colleagues found no significant association between surgical delay and upgrading on final specimen, lymph node invasion (LNI), pathologic locally advanced disease, or need for adjuvant therapy, according to findings published in the World Journal of Urology. The study also found no significant association between surgery delay or biochemical recurrence (BCR) across the whole study population and within risk groups.

“Our data support a safely deferred approach for PCa patients awaiting surgery in this time of COVID-19 pandemic.”

The study population had a median follow-up and surgical delay of 26.4 months and 3.3 months (range 2 to 5 months), respectively. The median surgical delay was significantly shorter among the patients with high-risk disease than those with intermediate-risk disease (3.5 vs 2.8 months). Patients had a median preoperative PSA level of 8.2 ng/mL. Results showed that 22.7%, 9.9%, and 46.9% had upgrading at final pathologic, LNI, and pathological locally advanced disease, respectively. In addition, 8.7% of patients experienced BCR. In a discussion of study limitations, Dr Diamand’s team acknowledged that the retrospective nature of their analysis introduces a potential selection and confounding bias with unknown factors that led physicians to opt for the most appropriate timing for surgery. “However, one must bear in mind that designing a prospective trial postponing treatment of oncologic patients is technically and ethically impossible.”

In addition, they pointed out that most of the patients underwent surgery within a period close to 3 months, “therefore, care must be taken to the interpretation of our results for longer treatment delays.”

Another limitation was the relatively short follow-up period, which could affect the number of BCR events, they noted.

The new findings are consistent with those of a recent study of 128,062 men with intermediate- and high-risk PCa who underwent RP from 2010 to 2016. In that study, Kevin B. Ginsburg, MD, of Wayne State University in Detroit, and collaborators found no significant difference in the odds of adverse pathology, upgrading, node positive disease, postoperative secondary treatments between men undergoing immediate RP (within 3 months of diagnosis) and any level of delay up to 12 months, according to findings published in The Journal of Urology. A subgroup analysis of men with grade group 4 and 5 PCa did not demonstrate an association between delayed RP and worse oncologic outcomes.

“As the United States continues to combat the COVID-19 pandemic, delays in nonemergent surgery such as RP are inevitable. … These data suggest that men who experience treatment delays due to the ongoing COVID-19 pandemic may not have worse oncologic outcomes and may provide reassurance to patients and urologists balancing care in the current pandemic,” the authors concluded.

In an editorial accompanying the study, Mark Tyson, MD, of Mayo Clinic Arizona in Scottsdale, wrote that despite study limitations “the authors should be commended on this timely analysis which will undoubtedly provide appropriate reassurance to patients and their loved ones during this time of great uncertainty and consternation.”

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May 1,” said medical oncologist Tomasz M. Beer, MD, professor of medicine at the Oregon Health & Science University (OSHU) in Portland, where he is deputy director of the OHSU Knight Cancer Institute. “During that time, prostate biopsies and even prostatectomies except for very aggressive cases were viewed as nonessential cases. But medical treatment for advanced cancer was universally treated as essential. We did not delay any hormonal therapy or chemotherapy or immunotherapy. And we did not delay participation and treatment in clinical trials. We were able to continue most of our clinical research.”

Routine visits for prostate cancer screening had largely been put on hold during March through May, and even men with elevated PSA may have delayed seeing urologists to arrange for a biopsy, Dr Beer said. Men who had a low-grade cancer found on a prepandemic biopsy may have held off on treatment because they know there generally is no urgency with these tumors. But caseloads are essentially back to what they were before the pandemic. “We’re all real busy again now,” he said.

Physicians at the institute transitioned many patient encounters to a virtual setting, Dr Beer said. “We see a lot of our patients by video [or] by phone if they have no access to video. But if they

need injections or infusions or imaging or blood tests, we have facilities set up to accommodate that, and they’ve continued to receive their treatment as scheduled.”

As a result of the COVID-19 crisis, Dr Beer explained that physicians made adjustments in specific PCa treatments.

For example, during the pandemic, most patients on hormonal therapy were switched to 6-month injections from 1-, 3-, and 4-month injections to decrease the number of patient visits.

Miami-Dade County In one of the newest COVID-19 hotspots, Florida’s Miami-Dade County (which as of August 30 had 156,038 and 2399 confirmed COVID-19 cases and deaths, respectively4), the outbreak prompted changes in how physicians at Sylvester Comprehensive Cancer Center in Miami provided PCa care as early as April.

“For a couple of weeks to a month beginning around mid-April, everything almost shut down completely,” said urologic oncologist Sanoj Punnen, MD, associate professor of urology at the University of Miami’s Miller School of Medicine. “We’ve had to restructure a lot of what we do.”

Prior to the pandemic, he saw patients from 8 AM to 5 PM, but now he sees them from 8 AM to noon, with p ­ riority

given to patients he “really needs to see in person for any acute issues and procedures.” Clinic staff schedule appointments to ensure patients do not wait around with others, Dr Punnen related. Patients wait in their cars until they receive a phone call telling them a clinic room is available for their appointment. His afternoons in clinic are spent conducting telehealth visits for patients he does not need to see in person. As a result of how his clinic functions, patients generally do not experience delays in care, he said.

“If a patient needs a biopsy, he can get it done pretty much as [if] we were at full capacity,” Dr Punnen said.

A Busy Period for Medical Oncologists Even in Minnesota, which was not especially hard hit by the pandemic, physicians had to alter their usual care of patients with PCa as a precaution, notably in March and April, according to Arpit Rao, MBBS, an assistant professor in the Division of Hematology, Oncology and Transplantation at the University of Minnesota in Minneapolis.

Dr Rao leads the genitourinary oncology clinical research program and the oncology quality and safety team for M Health Fairview system. According

to Dr Rao, some patients facing delayed RP or radiation therapy were placed on a few months of ADT as a therapeutic bridge until they could receive definitive treatment. The medical oncology department became busier during the pandemic, Dr Rao said, a trend he suspects is due in part to postponed PCa surgeries. Given the delay, men sought consultations with medical oncologists “just to make sure they’re exploring all the options,” he said.

“Before the pandemic, we had probably 16 to 20 patients in a day of clinic,” Dr Rao said. “During the pandemic, the volume has been 20% to 30% higher.”

For patients with metastatic PCa, he took steps to space visits farther apart when the pandemic hit. “I used to see everybody about once a month for oral novel antiandrogen therapy; now I see them every 6 to 8 weeks at this point,” Dr Rao said. “Whereas we used to get imaging every 3 months, now it’s every 4 to 6 months. Whether that’s going to have long-term consequences remains to be seen. But in the short term, we haven’t really experienced any s­ ignificant increases in complication rates.” For some patients already on ADT, he switched from 3-month to 6-month injections to decrease the number of patient visits. continued on page 24

Pandemic’s Effect on Prostate Cancer Research Variable

BY JODY A. CHARNOW

The pandemic has had less of an effect on clinical research at the Oregon

As with patient care, the pandemic has had an effect on prostate cancer (PCa)

Health & Science University (OSHU) in Portland. “By and large, we were able

research, but to varying degrees across the United States. At the Sylvester

to both continue to treat patients on study and continue new enrollments into

Comprehensive Cancer Center, clinical research slowed “because obviously

treatment studies,” said medical oncologist Tomasz M. Beer, MD, professor of

research isn’t given the same priority as clinical care,” said urologic oncologist

medicine at the OSHU and deputy director of the OHSU Knight Cancer Institute.

Sanoj Punnen, MD, who practices at the center and is associate professor of

Investigators discontinued some non-treatment studies in which there was no

urology at the University of Miami’s Miller School of Medicine. Many research

clear benefit to patients. Earlier in the pandemic, they stopped projects that

coordinators are still working from home, and that has affected clinical trial

involved gathering patient samples solely for laboratory research and had no

accrual. “We don’t really have the resources to get [patients] enrolled in trials and

direct effect on patient care, but these projects have since resumed, he said.

follow through with care,” Dr Punnen said. “As a result, I don’t think we’re seeing

At the University of Minnesota, COVID-19 had minimal effect on PCa research,

the accruals that we normally would.” He added, however, that the situation is

according to Arpit Rao, MBBS, an assistant professor in the Division of

“getting better week by week, and we’re almost back to where we used to be.”

Hematology, Oncology and Transplantation at the University of Minnesota in

The pandemic curtailed much of the PCa research at the University of

Minneapolis. “I think we’ve been very successful at keeping the pace of clinical

Washington, which had to suspend a number of clinical trials because of concern

research going,” he said, adding that his institution’s research program has actu-

about exposing patients to the COVID-19 coronavirus, said Daniel W. Lin, MD,

ally grown in terms of enrollment.

professor and chief of urologic oncology at the University of Washington in

“We’ve been able to publish, we’ve been able to contribute to [U.S. Food and

Seattle, where he also is director of the Institute for Prostate Cancer Research.

Drug Administration] approvals despite the pandemic,” Dr Rao said. “But there

These studies included dose-finding phase 1 trials and phase 3 trials where

have been challenges. At one point, we were basically doing twice as much

a “nonexperimental equivalent” treatment is available, he said. One of these

paperwork to get every single enrollment. Enrollments were halted university-

phase 3 trials is SWOG 1802, which is being conducted at sites throughout

wide, and you had to convince 3 tiers of research personnel to get a patient into

the United States. The trial is comparing standard systemic therapy alone (the

a clinical trial.”

nonexperimental equivalent) with standard systemic therapy plus definitive

He added, “Our patients have been very committed to clinical research. Many

treatment (RP or radiation) of the primary tumor (the experimental therapy) in

of them have been committed knowing full well that the research could benefit

patients with metastatic PCa.

future patients. That’s altruism at its finest.”

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SEPTEMBER/OCTOBER 2020 www.renalandurologynews.com

Prostate Cancer Care continued from page 20

Surgeries Resume ‘At Full Pace’ Although the pandemic led to an RP backlog, the situation has begun to normalize, according to Dr Rao. “We have been able to resume surgeries at full pace, as before the pandemic,” he said.

He kept in touch with many patients via telehealth, which he found useful but not optimal in some cases. “After the pandemic started, 80% of our visits were virtual,” he explained. “The pandemic offered us a glimpse into the future of oncology care and allowed us to understand the characteristics of patients and services that can be safely and effectively transitioned to a telehealth model, and of those for whom the traditional care model would continue to be the best approach.”

Telehealth is a major part of how City of Hope, a comprehensive cancer center in Duarte, California, is managing patients with PCa during the pandemic.

“COVID-19 has led many patients to be hesitant to come see their doctors due to perceived fear of exposure to the novel coronavirus,” said medical oncologist Yung Lyou, MD, PhD. As a result, patients undergoing chronic PSA surveillance or who were not on any active treatments that require a clinic visit — such as leuprolide injections or chemotherapy infusions — have asked to be converted to telehealth encounters.

“While City of Hope had a telemedicine program prior to the pandemic, the current situation prompted us to rapidly accelerate our planned telemedicine program expansion,” he said.

Reassuring Patients By Phone Increased use of telehealth was just one of the effects of the COVID-19 outbreak.

Dr Lyou said he had to reassure patients by telephone that his institution had strict infection-control measures in place to prevent COVID-19 transmission. “Many of my patients have felt anxious,” he said, “so I have had to make quite a few phone calls to inform them that at City of Hope, where the focus is primarily cancer patients, we take very strict precautions to limit the spread of COVID-19 within our facility. For example, I detail how all staff and patients are screened with a detailed questionnaire and temperature check prior to admission into the cancer center. Also, everyone is required to wear a mask and if they show up without one, we will issue a medical grade facemask at the door.”

Dr Lyou said physicians and other staff at City of Hope have been fortunate in

that their leadership has maintained adequate levels of personal protective equipment (PPE) for everyone.

Additionally, drive-through COVID-19 testing is readily available on the Duarte campus, with an approximately 4-hour turnaround time. “We perform in-house COVID-19 screening prior to all surgical procedures or hospital admissions,” Dr Lyou said. “These measures have greatly helped to limit our COVID-19 infection rates.”

To lower the risk of COVID-19 transmission, the City of Hope medical center limits the number of visitors.

“In the pre-COVID era, we used to see patients with their family members or caregivers,” he said. “However, due to COVID-19 visitor restrictions, with few exceptions, only the patient is allowed to enter the clinic for visits. As a workaround, we have been using telephone or videoconferencing with the other family members while we see patients to ensure everyone is included in the medical decision making [process].”

Dr Lyou said he has had to educate patients with PCa about their risk of contracting COVID-19. “One of the most common questions I get asked is, ‘As a prostate cancer patient, do I have a higher risk for COVID-19 compared to the general population?’”

He informs patients on chemotherapy that they may be at higher risk for infection because their treatment causes myelosuppression, but explains to ADT recipients that no definitive evidence exists showing that ADT causes immunosuppression. “As a result, they are most likely at the same risk as someone in their age group without prostate cancer,” he said.

Ramifications of Delayed Care Whether the delays in care caused by the pandemic will have an effect on PCa outcomes is unclear. Urologists and oncologists generally agree that deferring such medical procedures as prostate biopsies and prostate surgery for a few months will likely have no significant effect on oncologic outcomes in patients with low-risk PCa. As Dr Kapoor pointed out, PCa is generally a slow growing cancer compared with other genitourinary malignancies. “Frankly, I am much more worried about my patients with renal cell carcinoma and my patients with bladder cancer who may not have been able to come in than I am worried about the patients with prostate cancer,” he said.

Nevertheless, he said, “it would be naïve to believe that there were some patients whose pathology didn’t advance.”

Although the pandemic interrupted routine follow-up care such as PSA tests and prostate biopsies for patients on active surveillance, Dr Harris said, most of these patients have low- or very lowrisk cancer, “so a month or two probably isn’t going to make any difference as far as outcomes or changes in their disease pattern.”

Dr Punnen observed that patients with PCa usually do not need acute care, even those with metastatic disease on ADT. “If they miss receiving their ADT injection by a month or so, “it’s probably not going to have a huge impact,” Dr Punnen said.

Dr Rao pointed out, however, that many men are skipping primary care visits and not having PSA tests that could detect subclinical PCa. “They may end up presenting with locally advanced disease,” he said. Men with advanced PCa and asymptomatic bone metastases, especially those with aggressive disease, may progress to symptomatic disease and present with cancer-related complications as a result of putting off follow-up care for a few months, he said.

Regardless of COVID-19 outbreak severity, the pandemic has forced physicians in many parts of the United States to cut back substantially on PCa-related procedures at least for a few months, resulting in a backlog of cases. The situation appears to be brightening, however.

Even in places hard hit by COVID-19, physicians say they have been whittling away at their backlogs and returning to the clinical care they provided before the pandemic. It is too early to ascertain whether the delays in care caused by the pandemic will adversely affect patient outcomes long-term, but physicians generally agree that deferring prostate biopsies and definitive PCa treatment for a few months, at least for patients with low-risk PCa, will not significantly alter clinical outcomes. As healthcare services return to normal in many places, the pandemic rages on in various regions of the United States as investigators work on developing a COVID-19 vaccine and identifying safe and effective treatments. n

Survival Low in High-Risk MIUC Cases DESPITE INCREASING use of neoadjuvant treatment, the prognosis for patients with high-risk muscleinvasive urothelial carcinoma (MIUC) remains poor, data from a recent real-world study suggest.

From 2001 to 2013, the use of neoadjuvant treatment overall increased from 12% to 46% and use of cisplatinbased neoadjuvant chemotherapy increased from 5% to 38%, a team led by Alexandra Drakaki, MD, PhD, of UCLA, reported in Urologic Oncology.

Still, median overall survival (OS) and disease-free survival (DFS) were 23.1 and 13.5 months, respectively.

“Patients with high-risk MIUC continue to have a high risk of mortality within 2 years of extirpative surgery despite increasing use of cisplatin-based chemotherapy,” the authors concluded.

The most significant predictor of poor prognosis for both outcomes was American Joint Commission on Cancer (AJCC) stage 3B/4A disease, followed by non-White race and Charlson Comorbidity Index (CCI) of 2 or higher.

The study, which used data from the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database, included 665 patients with highrisk MIUC who underwent surgical resection from 2001 to 2013. Patients had a mean age of 75.5 years, 61% were men, and 91% were white.

Patients with stage 3A and 3B/4A disease had 40% and 87% shorter OS times, respectively, compared with patients who had stage 2 disease.

Patients with a CCI of 2 or higher had a 59% shorter OS time than those with a CCI lower than 2. In addition, nonWhite patients had a 50% shorter OS

REFERENCES 1. COVID-19: Data. New York City Health Department website. https://www1.nyc.gov/site/doh/covid/ covid-19-data.page. Updated August 30, 2020.

Accessed August 31, 2020.

2. United States Washington Overview. Johns Hopkins University & Medicine Coronavirus Resource Center website. https://coronavirus.jhu.edu/region/us/ washington. Updated August 30, 2020. Accessed August 31, 2020.

3. United States Oregon Overview. Johns Hopkins University & Medicine Coronavirus Resource Center website. https://coronavirus.jhu.edu/region/us/ oregon. Updated August 30, 2020. Accessed August 31, 2020.

4. United States Florida Overview. Johns Hopkins University & Medicine Coronavirus Resource Center website. https://coronavirus.jhu.edu/region/us/ florida. Updated August 30, 2020. Accessed August 31, 2020.

compared with White patients.

With regard to DFS, patients with AJCC stage 3A or stage 3B/4A had 18% and 77% shorter DFS times, respectively, compared with patients who had stage 2 disease. Patients with a CCI of 2 or higher had a 55% shorter DFS time than those with a CCI less than 2. Non-White patients had a 51% shorter DFS compared with White patients. ■

www.renalandurologynews.com SEPTEMBER/OCTOBER 2020

Renal & Urology News 25

New Index Useful As Muscle Mass Marker in HD Patients

Hyponatremia Occurs Often in COVID-19

A simplified creatinine index is reliable and can predict survival

HYPONATREMIA occurs in nearly one-third of patients hospitalized with COVID-19, and it independently predicts a higher risk of dying in the hospital, according to a recent study.

Of 4645 patients admitted to New York City hospitals with COVID19 from March 1 to May 13, 2020, hypo­ natremia (sodium level below 135 mmol/L) occurred in 1373 (30%) cases, Jennifer A. Frontera, MD, of the department of neurology at NYU Grossman School of Medicine in Brooklyn, New York, and colleagues reported online ahead of print in Critical Care Medicine. Of the patients with hyponatremia, 374 (27%) required invasive mechanical ventilation.

Mild, moderate, and severe hyponatremia (defined as admission sodium levels, in mmol/L, of 130 to 134, 121 to 129, and 120 or less, respectively) occurred in 1032 (22%), 305 (7%), and 36 (1%) of patients, respectively.

Each level of worsening hyponatremia was significantly associated with 43% increased odds of in-hospital death after adjusting for age, gender, race, body mass index, past medical history, admission laboratory abnormalities, and other variables, Dr Frontera and her colleagues reported.

Patients with moderate or severe hyponatremia had significant 83% increased odds of requiring invasive mechanical ventilation compared

BY JOHN SCHIESZER A SIMPLIFIED CREATININE index (SCI) is a reliable and inexpensive marker of muscle mass that can predict survival in patients on hemodialysis (HD), according to a new large observational study. “[The] SCI may fluctuate over time but remains in a quite acceptable variation in a clinical setting,” first author Bernard Canaud, MD, PhD, professor of nephrology at the School of Medicine at Montpellier University, Montpellier, France, told Renal & Urology News.

It is a simple, bedside, cost-effective parameter for muscle assessment — a complement to nutritional assessment — with a high predictive value not only for death risk, but for falls and fracture risk as well, particularly among the elderly, he said. SCI decline also is a strong indicator of hospitalization risk. “Monitoring SCI may be used as a physical activity indicator to guide and coach dialysis patients in order to trigger physical activity,” he said.

Surrogate of Active Muscle Mass The SCI reflects the creatinine generation rate of an individual HD patient and can account for such factors as dietary intake of meat. The SCI in mg/ kg/d is a surrogate of active muscle mass, meaning that it may diverge from instrumental assessment of muscle, such as with dual energy x-ray absorptiometry, because these tools estimate all physical components of muscle (collagen and fat tissue), Dr Canaud explained.

The study included 23,495 incident and prevalent HD patients documented in the MONitoring Dialysis Outcome (MONDO) Initiative, an international retrospective study cohort comprising chronic HD patients from 41 countries. Of these, 2194 (9.4%) died during follow-up. The mean age of the patients was 61 years, and 56.8% were male. The average dialysis vintage was 4.46 years.

Across all age strata, SCI values were statistically higher in men than women, with the highest SCI observed in men aged 18–29 years (23.8 mg/kg/d). In both sexes, SCI levels decreased with age, with the lowest SCI in patients

older than 80 years (men, 17.4 and women, 15.7 mg/kg/day), according to the investigators.

A total of 2194 patients (9.4%) died during follow-up. Each 1 mg/kg/d increase in SCI score was significantly associated with a 10% decreased risk of all-cause mortality in adjusted analyses, the investigators reported in Nephrology Dialysis Transplantation. In addition, the study found that declines in SCI score accelerated approximately 5 to 7 months prior to death.

The SCI reflects the creatinine generation rate of an individual hemodialysis patient.

The mean follow-up period was 265 days for patients who died and 337 days for those who survived. The patients who died tended to have lower SCI scores and a lower lean tissue index (LTI). They also had a lower post-HD weight and serum creatinine, albumin, and phosphate levels, as well as higher C-reactive protein levels and neutrophil:lymphocyte ratio.

“We consider the SCI advantageous since it uses routinely collected variables,” the authors concluded. “The SCI can thus be used to monitor a patient’s MM in a routine clinical setting and as a tool for population-level investigations.”

Results Not Surprising Lenar Tatios Yessayan MD, an associate professor in the department of nephrology at the University of Michigan in Ann Arbor, said the new study adds to the body of literature suggesting the SCI is valuable in assessing mortality outcomes. “I was not surprised by the results,” Dr Yessayan said. “Wellpreserved amount of muscle mass is known to be one of the strongest nutritional indicators for survival among ESRD population. The patients in the study were mostly European Caucasian, possibly limiting the generalizability of the SCI to a more diverse population such as [in] the US.”

Mark E. Williams, MD, director of dialysis operations at Beth Israel Deaconess Medical Center and senior staff physician at the Joslin Diabetes Center, both in Boston, said the SCI needs further investigation because the authors suggest that when albumin levels fall because of protein malnutrition, a decrease in SCI would have the advantage of being an earlier marker. “However, when secondary to inflammation, serum albumin levels are known to fall soon, within days to weeks,” Dr Williams said. “No data are present to determine how SCI levels behave in the same setting. There is ongoing review of the role of creatinine and creatinine reporting in diverse racial and ethnic groups, whereas the current report is limited to a somewhat homogeneous population.”

The new study was not designed to address whether the SCI could improve outcomes, but the SCI theoretically could trigger interventions, such as exercise or nutritional supplementation, which may be helpful in improving outcomes, he said.

Clinical Impact Unclear Orlando M. Gutiérrez, MD, professor of nephrology and associate director of the division of nephrology at the University of Alabama in Birmingham, said the study helps confirm that surrogate measures of muscle mass and nutrition are important markers of overall health in patients on maintenance HD. “This is clinically relevant, as muscle wasting and malnutrition are common problems in this population,” Dr Gutiérrez said.

“I think the results would be broadly applicable to a US or North American population. That being said, it is not clear to me that adding this index to other standard measures of nutrition in clinical practice would meaningfully improve morbidity or mortality.”

He added, “What we need to know in clinical practice is what information this index is adding above and beyond the standard measures collected as part of clinical care or whether it is basically providing the same information. If the latter is the case, then this index would likely not contribute much to improving morbidity or mortality.” ■

Almost one-third of COVID-19 patients had low sodium levels at hospital admission. with patients who had higher sodium levels, according to the investigators.

Patients with severe hyponatremia had significant 8-fold increased odds of encephalopathy.

The median time to resolution of hyponatremia (sodium level of 135 mmol/L or higher) was 1.05 days for the entire cohort, but increased along with hyponatremia severity, according to the investigators. The median time to normalization of sodium levels for patients with mild, moderate, and severe hyponatremia was 0.7, 2.1, and 3.9 days, respectively. ■

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Darolutamide for nmCRPC Prolongs OS Final analysis of the ARAMIS trial showed the drug decreased death risk by 31% compared with placebo

BY NATASHA PERSAUD DAROLUTAMIDE prolongs overall survival (OS) for patients with nonmetastatic castration-resistant prostate cancer (nmCRPC), according to a final analysis of the phase 3 Androgen Receptor Antagonizing Agent for Metastasis-Free Survival trial (ARAMIS; NCT02200614). An interim analysis conducted in 2019 confirmed longer metastasis-free survival. OS was a secondary endpoint in the trial.

OS at 3 years was 83% among darolutamide-treated patients compared with 77% among placebo-treated patients.

Darolutamide reduced death risk by a significant 31% in patients, Karim Fizazi, MD, PhD, of the Institute Gustave Roussy in Villejuif, France, and colleagues reported in the New England Journal of Medicine.

Darolutamide also significantly improved other secondary endpoints at 3 years compared with placebo. The median time to pain progression was 40.3 months in the darolutamide group compared with 25.4 months in the placebo arm. The proportion of patients who had not yet received their first cytotoxic chemotherapy was 83% among the darolutamide-treated patients compared with 75% in the placebo group.

The proportion of patients who did not

Improved Secondary Endpoints In addition to overall survival, darolutamide improved other secondary endpoints in the phase 3 ARAMIS trial, including time to pain progression, first use of cytotoxic chemotherapy, and first symptomatic skeletal event (SSE). Shown here are the proportions of patients who did not have these outcomes at 3 years.

100

■ Darolutamide ■ Placebo

83%

80 60 40

96%

92%

75%

53% 32%

20

Pain progression

First use of cytotoxic chemotherapy

First SSE

Source: Fizazi K, et al. Nonmetastatic, castration-resistant prostate cancer and survival with darolutamide. N Eng J Med. 2020;383:1040-1049.

experience a first symptomatic skeletal event was 96% in the darolutamide arm compared with 92% among placebo recipients. Darolutamide recipients had a significant 35%, 42%, and 52% decreased risk of pain progression, requiring cytotoxic chemotherapy, and first symptomatic skeletal event, respectively, compared with placebo.

“An overall survival benefit was observed even though more than half the patients in the placebo group received subsequent treatment with darolutamide or another life-prolonging therapy,” Dr Fizazi’s team wrote.

Over a median 29 months, adverse events (AEs) occurred in 85.7% of the darolutamide group, 79.2% of the placebo group, and 70% of placebo recipients who crossed over to darolutamide. No new long-term safety signals were observed since the interim analysis, and the proportion of patients who discontinued treatment remained the same (8.9% vs 8.7% with placebo).

All AEs increased slightly with longer exposure to darolutamide, as expected.

Fatigue was reported by 13.2% of the darolutamide group compared with 8.3% of placebo group. Bone fracture

occurred in a higher proportion of darolutamide-treated patients (5.5% vs 3.6%), but this difference decreased after adjustment for duration of drug exposure. All other AEs were reported by approximately similar proportions of both groups, including falls, seizures, mental impairment, and hypertension.

Other androgen receptor inhibitors have shown higher incidences of central nervous system-related adverse events and hypertension compared with placebo, the authors noted.

“This updated analysis of the ARAMIS trial confirms the low potential for central nervous system-related effects expected with darolutamide, which has been postulated to be due to the very low penetration of the bloodbrain barrier that has been reported in preclinical and clinical trials of darolutamide,” Dr Fizazi’s team pointed out.

In the trial, investigators randomly assigned 955 patients to darolutamide (600 mg twice daily), a structurally distinct androgen receptor inhibitor, and 554 patients to placebo, while patients continued to receive androgen deprivation therapy. More than half of placebo recipients later crossed over to receive darolutamide or other life-prolonging therapy (eg, chemotherapy, another antiandrogen, or sipuleucel-T). ■

CVD Deaths Declining in Young Dialysis Patients THE RISK OF DYING from cardiovascular disease (CVD) has been declining among children and young adults starting dialysis, according to a new study.

Elaine Ku, MD, MAS, of the University of California, San Francisco, and colleagues used the US Renal Data System to identify 80,189 patients younger than 30 years (median 24 years) who initiated dialysis from 1995 to 2015. During a median of 14.3 years of follow-up, 16,179 died. Of these, 6505 (40.2%) died from CVD-related causes.

In adjusted analyses, risk of CVDrelated death was stable initially but became significantly lower after 2006 compared with 1995 among those starting dialysis either as children (26% decreased risk) or young adults (10% decreased risk), Dr Ku’s team reported in JAMA Network Open.

Dr Ku and her colleagues defined children as patients less than 18 years old and young adults as those aged 18 to 30 years.

“To our knowledge, our study is among the first to compare and contrast temporal trends and case-specific mortality risk in a cohort of children vs young adults starting dialysis.”

The risk of dying from cardiovascular causes decreased from 1995 to 2015.

Comparing 2015 with 1995, the risk of sudden cardiac death (SCD) improved steadily in all age groups, but to a greater degree in children (69% decreased risk) compared with young adults (36%

decreased risk). The risk of dying from a myocardial infarction (MI) was a significant 30% lower after 2005 compared with 1995 among young adults, but among children, the difference in risk of dying from an MI was not significantly different during most of the follow-up duration, according to the investigators.

The study population was 45.2% female, 36.8% Black, 19.3% Hispanic White. The most common cause of ESKD in the cohort was glomerulonephritis (37.4%).

Compared with the overall cohort, patients who died were older when they started dialysis (24.3 vs 22.5 years).

They also were more likely to be female and Black and to have diabetes, and less likely to have glomerulonephritis as their cause of kidney failure.

“Given that CVD remains the most common cause of death in this

­ opulation, strategies to further improve p CVD risk profile in this young population are needed to enhance survival, and modification of nontraditional CV risk factors may be needed to ensure continued improvements in outcomes for young populations starting on dialysis.”

Although the study has a number of strengths, such as a large sample size, a large number of events, and inclusion of both children and young adults, it also had limitations. For example, the cause of death was missing from approximately 8% of patients, and misclassification of causes of death may have occurred, Dr Ku and her colleagues pointed out. They also acknowledged a lack of “more granular data that may be needed to determine exact reasons for changes in temporal trends in mortality over time, or changes in treatment of cardiovascular risk factors.” ■

www.renalandurologynews.com SEPTEMBER/OCTOBER 2020

Renal & Urology News 27

Ethical Issues in Medicine T

he COVID-19 pandemic has uncovered a recurring and particular ethical problem in medicine. In the face of serious illnesses for which no cure exists or pharmacologic treatment options are limited, many patients will demand better and faster access to unproven treatments while many scientists and physicians contend that more rigorous research is needed to establish safe, effective treatments.

These lines are obviously arbitrary — not all patients and physicians fit neatly into these categories — but the ethical tension remains. Bringing an urgently needed effective medication to the public quickly and safely during a pandemic involves difficult tradeoffs.

This tension surfaced during the AIDS epidemic, when patients and activists pushed the US government to accelerate research and expand access to potential but uncertain HIV treatments.

A similar scenario unfolded again during the COVID-19 pandemic as arguments surfaced for wider access to potentially beneficial treatments at the same time as others cautioned against exuberance for unproven treatments.

For physicians who were faced with choices earlier this year about whether to prescribe unproven treatments for COVID-19 like hydroxychloroquine

broader authority to practice medicine.

Because HQ was already FDA approved for use in malaria prophylaxis and lupus among other indications, physicians had the legal authority to prescribe it for both COVID-19 treatment and prophylaxis if they believed it was medially indicated.

As clinical practice guidelines were being developed, individual physicians and hospital guideline committees were beset with figuring how and when they would prescribe HQ for appropriate patients.

The medical literature is now replete with HQ’s significant limitations and risks, particularly its lack of beneficial effect on hospitalizations, intubation, and mortality. However, an ethics perspective may have provided some guidance for thinking rigorously and constructively about how to prescribe this medication during a public health emergency. Central to this process is to identify and then assess the known and unknown risks, benefits, and alternatives available at the time. Once those are acknowledged, weighed, and clearly communicated, clinicians can more easily justify an ethically strong position.

Many of the risks of HQ were wellestablished from its prior FDA approval for indicated conditions. Patients with lupus, rheumatoid arthritis, and malaria had been prescribed this medication

For clinicians, the primary responsibility is to the care and treatment of the patient in front of them, not to the public.

(HQ), there were generally 2 options available. The first was the FDA emergency use authorization (EUA), which provided not approval, but temporary authorization due to the public health emergency on the basis that the medication may be effective and that the benefits outweighed the risks. The second option was to prescribe HQ “off-label,” that is, based on a physician’s authority to prescribe FDA-approved medications for an unapproved use as part of their

sometimes for years, and the risks were well known and understood. Others in the medical community asserted this, and thus the potential for benefit during a public health emergency, even if unknown, was central to saving lives.

However, a counterpoint to this assertion is that this claim suffers from an inadequate appreciation of risk.

First, if patients relied on an unproven medical treatment like HQ, it might reduce their likelihood of engaging in

© WILDPIXEL / GETTY IMAGES

Urgent need for COVID-19 treatment presents physicians with a dilemma when no proven therapy exists BY DAVID J. ALFANDRE, MD, MSPH

Physicians could be in a tough spot when deciding on how to treat patients with COVID-19.

effective preventive behavioral interventions like physical distancing, hand washing, and masking, which are all known to reduce COVID-19 transmission. Second, although the risks of HQ were understood for FDA approved medical conditions, its risks in acute COVID-19 illness were unknown. Third, off-label prescribing was credited with reducing the number of eligible patients for ongoing COVID-19 treatment research studies. Although the effect on research wasn’t a risk to the individual patient, it had important public health risks, as an absence of research on HQ in well-designed studies was needed to identify how best to treat all patients with COVID-19. This last point highlights the ongoing ethical tension between the needs of individual patients and those of the community, and how a pandemic can shape those challenges. For clinicians, the primary responsibility is to the care and treatment of the patient in front of them, not to the public. Patients depend on and expect this from their physicians because it is central to building the trust needed for high-quality patient care. But this duty is not without limits and may be harder to justify when there is a disproportionately large benefit to the community compared to individual patients during a pandemic.

Finally, both patients and physicians are prone to the cognitive error of commission bias—that is, the belief that doing nothing is always worse than doing something. It is the misconception that an action like prescribing medication could only reliably produce benefit, not harm. It’s unknown if this bias interfered with clinical reasoning about HQ, which may have been heightened during the pandemic.

Enhancing access to untested treatments while providing them safely and effectively is an ongoing challenge, one we hope will get better at over time.

Thoughtful attention to the known and unknown risks and benefits with attention to our own biases can be a helpful start to making more progress. ■ David J. Alfandre MD, MSPH, is a healthcare ethicist for the National Center for Ethics in Health Care (NCEHC) at the Department of Veterans Affairs (VA) and an Associate Professor in the Department of Medicine and the Department of Population Health at the NYU School of Medicine in New York.

The views expressed in this article are those of the author and do not necessarily reflect the position or policy of the NCEHC or the VA.

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Practice Management B

eing paid for services is a perennial challenge for nearly all healthcare organizations, with billions of dollars each year going unpaid. During the COVID19 pandemic, providers got hit hard financially and many lost their health insurance, so practices might want to focus more effort on collections.

Understanding the psychology of collecting money is a good way to start.

A combination of a human touch and technology can help the process along.

Mental Accounting People generally expect to pay in full for a massage from a spa or a haircut offered by a stylist. When they buy a car or house, they sign a payment plan. But healthcare tends to be an area where people balk at paying their bills. This could be partly due to what is called mental accounting, the theory that people file money into different buckets based on their goals and values, according to an article published on behavioraleconomics.com.

Typically, people are more willing to spend on pleasurable activities — like $100 for dinner and a movie — than on a $100 doctor bill.

“Human connection is desperately what we all need right now,” said

wanted to check in to see how you are doing because I see you haven’t paid your bill. I wanted to see how I can help you. Is there something that will work for you to get this cleared up?”

She also pointed to a few behavioral theories to keep in mind when working on collections: • People recall the most recent things they see more than past ones.

Sending frequent reminders can keep a practice at the top of a person’s list of bills to pay.

• People are more concerned with losses than gains, meaning they will pay off small debts more quickly than large ones. Focusing on collecting the least likely debts to be paid may help increase accounts receivables.

• People hate to lose benefits — like a 3% credit for paying a fee early or in cash. Letting patients know they are about to lose that benefit may motivate them to pay their bill.

Credit Cards On File Technology also offers solutions for increasing collections. For instance, people are perfectly fine having a credit card on file for their monthly Netflix subscription or to make purchases on Amazon.com easier. But

Typically, people are more willing to spend on pleasurable activities — like $100 for dinner and a movie — than on a $100 doctor bill Vicki Seredich, chief finance officer of Lockstep, the creator of the accounts receivable program Anytime Collect.

“If we treat people as humans, we can produce a much better result than collections or a demanding phone call.

People always pay the people they like first.”

Seredich recommends trying to find out what the issue or barrier is for patients paying their bills. When calling, she suggests verbiage like this: “I

healthcare providers are reticent to follow this practice.

“People used to be highly suspicious of keeping a credit card on file,” said Allyson Howard, assistant director of marketing for Health iPass. “But people have been conditioned to do it now.

Doctors are hesitant, but most patients will be okay with it.”

Having a card on file can move collections numbers to as much as 97%, Howard said. Most patients are willing

© ANTONIOGUILLEM / GETTY IMAGES

Using psychology to connect with patients on a personal level could improve practices’ ability to collect debts BY TAMMY WORTH

Working with patients to create payment plans is one way to improve collections.

to keep a card on file for charges under $200. That is particularly useful for providers that provide frequent, inexpensive treatments like shots at an allergist.

“A huge amount of uncollected revenue comes from smaller balances,” she said.

Other Options Seredich said a multipronged approach is best for collections. In a recent benchmark report of healthcare accounts receivable, her organization found that top performers were calling patients, using automated triggers, and manually sending emails.

She said she endorses working directly with patients to create payment plans that work well for them. “This way, they don’t feel like they have to put their health on the back burner or have to worry about buying groceries or getting healthcare during a pandemic,” she said.

COVID-19 Impact The rise in telehealth and changes to office practices brought on by the COVID-19 pandemic also provide an opportunity for technology to improve collections. Organizations like Health

iPass offer a program that is, in essence, a virtual waiting room. Instead of filling out paperwork, patients can receive a text with a link to a page where they can enter their demographic information, take a picture of their insurance card, pay a copay, and see their residual balance. This kind of technology can be used prior to an in-office visit or just before a virtual one.

“A practice needs to make sure [patients] have the ability to call, email and text — all 3,” Howard said. “Ask them what their preferred method of communication is and stick with that.”

Patient preferences can depend on several factors, including age. Younger people tend to respond better to texts; for someone a little older, phone calls might be best. Email, she said, tends to be somewhat universal.

“It is a tough time now for the masses, and doctors have so much more to worry about than we think about,” Howard said. “And they need to understand there are resources out there to help them and perform these tasks that are necessary without them having to worry about it.” ■ Tammy Worth is a freelance medical journalist based in Blue Springs, MO.