Renal & Urology News - Fall 2022 Edition

MDT Bene cial in Oligometastatic PCa

BY JOHN SCHIESZER

ADDINGMETASTASIS-directed therapy (MDT) with radiation to intermittent hormone therapy for oligometastatic prostate cancer (PCa) improves outcomes and allows for greater time off hormone therapy, investigators reported at the 2022 Annual Meeting of the American Society for Radiation Oncology (ASTRO). Results suggest that this approach has the potential to improve patients’ quality of life (QoL).

The finding is from the phase 2 EXTEND trial, the first randomized trial to evaluate MDT with hormone therapy in this disease state.

Investigators randomly assigned 87 patients with 5 or fewer metastases to receive MDT plus hormone therapy

Adding CN Ups Survival in mRCC

BY JODY A. CHARNOW

CYTOREDUCTIVE nephrectomy (CN) in conjunction with immune checkpoint inhibitor (ICI) therapy for metastatic renal cell carcinoma (mRCC) is associated with significantly longer overall survival compared with ICI therapy alone, according to investigators.

Compared with patients who received ICI therapy alone, those treated with CN plus ICI therapy had a median overall survival of 56.3 months compared with 19.1 months for those treated with ICI therapy alone, a team led by Sarah P. Psutka, MD, MS, of the Fred Hutchinson Cancer Center at the University of Washington in Seattle, reported in Urologic Oncology. In

adjusted analyses, the combination therapy arm had a signi cant 67% reduction in the risk for all-cause mortality compared with the monotherapy arm.

ICI therapy was used as rst-line and second-line treatment in 28.1% and 17.4% of patients, respectively, and third-line or subsequent lines of therapy in 54.5% of patients. The investigators observed a survival bene t in patients who received an ICI in any line of therapy.

Dr Psutka and colleagues conducted a subgroup analysis of patients who received an ICI as rst-line therapy. In this group, the median overall survival was not reached in patients who underwent CN compared with 14.9 months in those who received ICI therapy

SGLT2i Use May Reduce Stone Risk

BY NATASHA PERSAUD EMPAGLIFLOZINMAY

reduce the risk of nephrolithiasis in patients with type 2 diabetes, according to new research presented at Kidney Week 2022, the annual meeting of the American Society of Nephrology, in Orlando, Florida.

Using 2013-2019 claims data from 2 private health plans and Medicare, investigators identi ed 102,275 pairs of matched adults with type 2 diabetes initiating empagli ozin (a sodium-glucose cotransporter-2 inhibitor; SGLT2i) or a dipeptidyl peptidase 4 inhibitor (DPP4i) and 115,489 pairs of matched adults initiating empagli ozin or a glucagon-like peptide 1 receptor agonist (GLP1RA).

Over a mean follow-up of approximately 8 months on treatment, the risk of a nephrolithiasis diagnosis was a signi cant 28% and 27% lower in the empagli ozin group compared with the DPP4i group and the GLP1RA

(43 patients) or hormone therapy alone (44 patients). All patients underwent a hormone break 6 months after randomization. During a median followup period of 22.1 months, 41 patients experienced disease progression. The median progression-free survival (PFS) was not reached in the combination arm compared with 15.8 months in the hormone monotherapy group. Adding MDT to hormone therapy was signicantly associated with a 75% decreased risk for disease progression.

“The effect of radiation therapy in extending PFS was very large,” said lead author Chad Tang, MD, Associate Professor of Radiation Oncology at The University of Texas MD Anderson

METASTASIS-DIRECTED THERAPY has a role in treating oligometastatic prostate cancer.

©

FROM THE MEDICAL DIRECTOR

The Ever-Expanding Role of Advanced Practitioners

In recent years, advanced practitioners have emerged as an important workforce in nephrology and urology. Advanced practitioners include, but are not limited to, nurse practitioners and physician assistants. Their traditional function was thought to be limited to extending the role of physicians in mostly ambulatory settings. But today, advanced practitioners play an increasingly important role in direct patient care in nearly all areas of health services. In nephrology, an increased need for advanced practitioners appeared in the early 2000s, when the Medicare ESRD program’s Conditions for Coverage started requiring at least 4 visits per month to be eligible for full dialysis physician fee payments. Many nephrology groups arrange several monthly dialysis rounds by advanced practitioners under the short-visit billing code in addition to a monthly comprehensive dialysis visit by the nephrologist of record to ensure regulatory compliance. Nondialysis ambulatory clinics use advanced practitioners to provide care to less complicated cases of CKD progression. This care can encompass preparation of transition to dialysis therapy. As a result of increasing nephrology inpatient volumes and a shortage of recently trained nephrologists, inpatient advanced practitioners have emerged as important members of the nephrology consult service in both academic and community practices. Whereas some consult groups may prefer to assign advanced practitioners to more stable cases, there are highly capable advanced practice providers who can provide more sophisticated and critical care nephrology consults with minimal oversight by a nephrologist.

In the field of renal transplantation, advanced practitioners have exhibited a wide-ranging function across all practice areas, including kidney transplant eligibility workups, sensitive communications among family members and interdisciplinary team members and other providers, and after-hours and weekend calls for deceased-donor kidney offers. More and more advanced practitioners who specialize in kidney transplantation are making multidisciplinary inpatient rounds along with transplant surgeons—and often in place of the transplant nephrologist. These providers perform focused workups for acute rejection, suspected infections, and urologic complications of renal transplantation. Urologists, too, work not infrequently with advanced practitioners, although questions remain about the most efficient ways to integrate them from a regulatory and practice management approach, according to an American Urological Association position paper published in January 2022.

The need for expanded multidisciplinary teams in nephrology and urology in contemporary practice should be recognized and advocated, with the inclusion of dedicated advanced practitioners to ensure a more effective and efficient kidney health team.

Kam Kalantar-Zadeh, MD, PhD, MPH Professor & Chief, Division of Nephrology, Hypertension & Kidney Transplantation UC

Irvine School of Medicine, Orange, CA Twitter/Facebook: @KamKalantar

EDITORIAL ADVISORY BOARD

Medical Director, Urology

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

Urologists

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

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

Stanton Honig, MD 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

Medical Director, Nephrology

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

David S. Goldfarb, MD

Professor, Department of Medicine Clinical Chief New York University Langone Medical Center Chief of Nephrology NY Harbor VA Medical Center

Csaba P. Kovesdy, MD

Chief of Nephrology Memphis VA Medical Center

Fred Hatch Professor of Medicine

University of Tennessee Health Science Center Memphis

Edgar V. Lerma, MD

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

Renal & Urology News Staff

Editor Jody A. Charnow

Web editor Natasha Persaud

Production editor Kim Daigneau

Group creative director Jennifer Dvoretz

Senior production manager Krassi Varbanov

Vice president, sales operations and production Louise Morrin Boyle

National accounts manager William Canning

Editorial director, Haymarket Oncology Lauren Burke

Vice president, content, medical communications Kathleen Walsh Tulley

Chief commercial officer James Burke, RPh

President, medical communications Michael Graziani

Chairman & CEO, Haymarket Media Inc. Lee Maniscalco

Renal & Urology News (ISSN 1550-9478) Volume 21, Number 4. Published quarterly 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 © 2022.

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Urology

17 More PSA Screening Tied to Lower mPCa Incidence

A study of VA medical facilities showed that each 10% increase in PSA screening rate was signi cantly associated with a 9% decrease in the incidence of metastatic prostate cancer.

20 PSMA Status of CTCs Could Guide mCRPC Therapy

PSMA expression on circulating tumor cells is fairly uniform in some patients and heterogeneous in others.

22 Shift in Metastatic Prostate Cancer Care Advocated

More aggressive treatment at an earlier stage recommended to achieve larger improvements in survival.

25 Post-RCC Treatment ESKD Risk Factors

Identifed

Radical nephrectomy, CKD, male sex, and higher T-stage found to increase the likelihood of end-stage kidney disease.

Nephrology

14 No Need to Stop RAS Inhibitors in Advanced CKD

Discontinuing the medications does not result in a clinically relevant change in eGFR, investigators report.

14 Anemia Tied to Dementia Risk in CKD

Moderate or severe anemia increases the likelihood of dementia by 23% among patients aged 65 years or older, a study found.

15 Nephrologists Lag in SGLT2i Prescribing

Although use of sodium-glucose cotransporter-2 inhibitors is on the rise, they only account for a small fraction of prescriptions.

16 Budesonide May Ease IgA Nephropathy

The medication improves the UPCR and maintains eGFR, a phase 3 trial demonstrated.

CALENDAR

Editor’s note: The 2023 conference listings below include information provided by the sponsoring organizations on their websites as this issue went to press.

ASCO Genitourinary Cancers Symposium February 16-18 San Francisco, CA

Annual Dialysis Conference March 3-6 Kansas City, MO

European Association of Urology Annual Congress March 10-13 Milan, Italy

National Kidney Foundation Spring Clinical Meetings April 11-15 Austin, TX

American Urological Association Annual Meeting April 28-May 1 Chicago, IL

American Transplant Congress June 3-7 San Diego, CA

European Renal Association Annual Congress June 15-18 Milan, Italy

Some doctors still ‘hold the good stuff in their back pocket’ and avoid or delay the most effective options up front.

News in Brief

AKI During ICI Therapy

Tied to Higher Mortality

Patients with acute kidney injury (AKI) during immune checkpoint inhibitor (ICI) therapy have an increased risk for death, a recent study show.

Investigators performed a metaanalysis of 7 studies including 895 patients with AKI and 2872 patients without AKI receiving ICIs. In analyses of 5 studies, AKI during ICI therapy was significantly associated with a 42% increased risk of all-cause mortality compared with no AKI, Mehmet Kanbay, MD, of Koc University School of Medicine in Istanbul, Turkey, and colleagues reported in the Clinical Kidney Journal

TMP-SMX vs Amoxicillin Raises Hyperkalemia Risk

Trimethoprim-sulfamethoxazole (TMPSMX) therapy is associated with a higher risk for a hospital encounter with hyperkalemia compared with amoxicillin therapy, investigators reported in Nephrology Dialysis Transplantation TMP-SMX can cause hyperkalemia by decreasing potassium excretion.

In a population-based cohort study of patients aged 66 years or

older, Y. Joseph Hwang, MD, of Johns Hopkins University School of Medicine in Baltimore, Maryland, and colleagues compared the hyperkalemia rate between 58,999 patients newly treated with TMP-SMX and the same number of patients newly treated with amoxicillin. Hospital encounters with hyperkalemia were 3.3 times more likely for patients treated with TMP-SMX vs amoxicillin.

Cryoablation Outcomes in Localized

PCa ‘Excellent’

Primary whole gland cryoablation of the prostate in men with localized prostate cancer (PCa) is associated with “excellent” oncologic and functional outcomes, according to study findings published recently in Cancer The study included 260 men who had the procedure for localized PCa. The median follow-up was 107 months. The 10-year rates of biochemical recurrence-free survival, failurefree survival, and metastasis-free survival were 84%, 66%, and 96%, respectively, Wei Phin Tan, MD, of Duke University Medical Center in Durham, North Carolina, and colleagues reported. Stress urinary incontinence occurred in 5 patients (2%).

Cancer Mortality Declining

Glomerular Disease Ups Fracture Risk in Children

Fractures are more common among children with glomerular disease, especially girls, compared with the general pediatric population, study findings suggest. In a study comparing 4598 children with glomerular disease and 553,624 patients in the general pediatric population, girls with glomerular disease were 1.6 times more likely than those in the general pediatric cohort to experience any type of fracture, a team led by Michelle Denburg, MD, of the Children’s Hospital of Philadelphia, reported in the Journal of the American Society of Nephrology The difference between boys with glomerular disease and those in the general pediatric cohort was not statistically significant.

“This sex difference warrants further investigation and could be due to differential effects of glomerular disease on bone quality in girls versus boys,” Dr Denburg and colleagues wrote. “Sex differences in growth-related indices of bone quality, such as greater bone size and strength across growth in boys, may render girls more vulnerable to the effects of glomerular disease.”

Neoadjuvant Combo May Be Beneficial in High-Risk PCa

Neoadjuvant degarelix with apalutamide prior to radical prostatectomy (RP) for high-risk prostate cancer is associated with improved pathologic response compared with degarelix alone, investigators reported in European Urology

In the ARNEO randomized phase 2 trial, 45 patients received degarelix plus apalutamide and 44 received degarelix plus matching placebo (control group) for 12 weeks followed by RP. The degarelix-apalutamide arm achieved a higher rate of minimal residual disease (residual cancer burden of 0.25 cm3 or less at final pathology) than the control group (38% vs 9.1%), a team led by Steven Joniau, MD, of University Hospitals Leuven in Belgium, reported.

RCC-Specific Mortality More Likely After Ablation vs PN

Among patients with T1a renal cell carcinoma (RCC), those who undergo local tumor destruction (LTD), such as ablation, rather than partial nephrectomy (PN) have a higher risk for cancer-specific death, a new study finds.

Using the 2004-2018 Surveillance, Epidemiology, and End Results (SEER) database, investigators identified 42,920 patients with T1a RCC, of whom 35,984 underwent PN and 5936 underwent LTD (ie, cryoablation or heat-based thermal ablation). They propensity-score-matched 5352 patients in the PN group and 5352 patients in the LTD group by RCC histological subtype, tumor size, tumor grade, and age.

The 10-year cancer-specific mortality rate was higher in the LTD group: 8.7% vs 5.5% for PN. In multivariable models, the LTD group with T1a RCC had a significant 58% increased risk of cancer-specific death compared with the PN group, Gabriele Sorce, MD, of Urological Research Institute, IRCCS San Raffaele Scientific Institute in Milan, Italy, and colleagues reported in European Urology Focus Cancer-specific mortality risk varied by tumor size, increasing significantly by 1.5-fold for tumors 3 cm or smaller and 1.7-fold for tumors 3.1-4.0 cm.

MDT beneficial

Cancer Center in Houston. “Many patients who received radiation therapy and hormone therapy continue to be free of all evidence of disease at last follow-up despite being off hormone therapy for many years. The effect of radiation therapy in extending PFS also seemed to hold across subgroups.”

A Promising Strategy

He added, “Importantly, the time that men had eugonad testosterone was also increased by the addition of radiation therapy. Intermittent hormone therapy and radiation therapy may be a promising strategy to minimize hormone therapy exposure while maintaining excellent disease control in men with oligometastatic prostate cancer.”

Men received hormone therapy for at least 2 months before starting the trial, and each stopped hormone therapy for a planned break 6 months after they started. Patients restarted

SGLT2i use and stone risk

continued from page 1

group, respectively, Julie M. Paik, MD, ScD, MPH, of Brigham and Women’s Hospital in Boston, Massachusetts, reported on behalf of her team. In absolute terms, empagliflozin use was associated with 6.2 and 6.0 fewer stone cases per 1000 person-years than DPP4i and GLP1RA use, respectively.

“In routine care, empagliflozin use was associated with a reduced risk of nephrolithiasis,” Dr Paik told Renal & Urology News. “Clinicians might consider prescribing empagliflozin to patients with diabetes at higher risk of developing kidney stones who meet other indications for an SGLT2 inhibitor.”

CN ups survival in mRCC

continued from page 1

alone. On multivariable analysis, the addition of CN to ICI therapy was significantly associated with an 81% decreased risk of death compared with ICI therapy alone.

Higher Complete Response Rates

Addition of CN to treatment generated higher rates of complete response following first-line ICI therapy without higher rates of grade 3-4 adverse effects, according to investigators.

“Our data support the continued use of CN in carefully selected patients

hormone therapy at the time of disease progression. Hormone therapy consisted of a luteinizing hormonereleasing hormone agonist/antagonist with or without a second-generation androgen-receptor targeting agent.

As a primary secondary endpoint, MDT significantly improved time from recovery of eugonad testosterone

difference that did not seem to vary substantially among important subgroups” Dr Tang said. “For urologists, the take-home point is that with careful management using radiation and hormone therapy there exists the potential to convert metastatic prostate cancer, initially diagnosed with oligometastatic disease to a chronic disease treatable with intermittent treatments that maintain QoL.”

A Well-Conducted Trial

levels (above 150 ng/dL) to progression (median not reached vs 6.1 months in the monotherapy arm).

The investigators observed grade 3 toxicities in 3 patients in each study arm.

“The main weakness [of the study] is that is a relatively small study and there is heterogeneity; however, despite this heterogeneity we saw a large significant

She added, “Real-world evidence and [randomized controlled trial] data together can help advance our understanding of agents for stone prevention.”

The latest study adds to previous findings suggesting that SGLT2i therapy may protect against kidney stones. A study conducted in Denmark by Kasper B. Kristensen, MD, and colleagues found that patients treated with SGLT2is had a significant 49% lower risk for nephrolithiasis versus GLP1RA recipients in a propensity score-matched analysis, according to a 2021 report in Diabetologia. The nephrolithiasis rate was 2.0 per 1000 personyears in the SGLT2i group compared with 4.0 per 1000 person-years in the GLP1RA group.

with mRCC undergoing treatment with contemporary immunotherapy,” Dr Psutka and colleagues concluded.

The study cohort consisted of 367 patients—232 who underwent CN and received ICI therapy and 135 who received ICI therapy alone. Survival had a median follow-up of 28.4 months. Of the patients undergoing CN, 202 (87%) underwent upfront CN and 30 (13%) deferred the surgery. The investigators found no significant differences in overall survival between patients who had upfront CN and deferred CN.

The authors acknowledged the study’s limitations. These included its

Gerald L. Andriole, MD, Professor of Urology and Director of Urology for the National Capital Region of the Johns Hopkins Medicine’s Brady Urological Institute, said the trial was well conducted and provides further evidence that MDT appears to be beneficial for men with oligometastatic PCa. In addition to prolonging PFS, the MDT group spent more time off of intermittent hormone therapy, with longer intervals of normal testosterone levels, which should translate into better overall QoL.

In another study, published in The Journal of Clinical Endocrinology & Metabolism, investigators reached similar conclusions based on data from randomized clinical trials. They pooled data from 20 phase I-IV trials involving 15,081 patients with type 2 diabetes randomly assigned to receive empagliflozin or placebo.

Empagliflozin use was significantly associated with a 36% reduced risk of stones with 1.01 vs 0.63 stone events occurring per 100 patient-years in the placebo and empagliflozin group, respectively, Priyadarshini Balasubramanian, MD, of Yale School of Medicine in New Haven, Connecticut, and colleagues reported. The dose and median exposure of

retrospective design and observational nature “with the attendant impacts of selection bias, unmeasured confounding, and variation in institutional and

Howard Sandler, MD, Chair of the Department of Radiation Oncology at Cedars-Sinai in Los Angeles, California, and president-elect of ASTRO, noted that the current study shows a substantial delay in time to progression with MDT. “I was surprised pleasantly with the magnitude of the effect,” Dr Sandler said. “Delaying progression is clinically meaningful to prostate cancer patients since progression leads to more hormone therapy or other impacts of cancer dissemination.”

Patient-Reported Outcomes Needed

This type of study is highly valued because it is randomized, but more research is warranted. “In this exact space, it would be nice to see patient reported QoL outcomes to confirm that QoL was improved with MDT,” he said. “Also, more information on the immune system impact by MDT would be interesting regarding the potential mechanism of action of MDT in delaying progression.” ■

empagliflozin was 10 mg or 25 mg for 549 days.

“One proposed mechanism for decreased stone risk with SGLT2 inhibitors is increased urinary flow rate

provider practice patterns over time which may influence both the generalizability and impact the validity of the results,” they wrote.

due to osmotic diuresis from glucosuria and natriuresis and consequent changes in urinary concentrations of lithogenic substances,” Dr Balasubramanian’s team wrote. ■

Another limitation was a lack of granular patient-level data and modest cohort size that prevented them from using propensity score matching techniques in their analysis, they noted.

Despite study limitations, the authors stated that their findings “add to the emerging literature regarding optimal management of patients with mRCC in contemporary practice. The speed at which immunotherapy has surpassed targeted treatment has left guidance regarding surgery for mRCC unclear,” the authors wrote. “Timely retrospective analyses offer crucial direction until knowledge gaps can be filled with large prospective clinical trials.” ■

Metastasis-directed therapy enabled men to have more time off hormone therapy.

Empagliflozin lowered nephrolithiasis risk by 28% compared with a DPP4i, a study found.

Use of cytoreductive nephrectomy with ICI therapy reduced death risk by 67%.

SGLT2 Inhibitor Empagliflozin Lowers Risk for CKD Progression, Data Show

EMPAGLIFLOZIN DECREASES the risk for chronic kidney disease (CKD) progression or death from cardiovascular cases in patients with or without diabetes, according to findings from the EMPAKIDNEY trial presented at Kidney Week 2022 and simultaneously published in the New England Journal of Medicine Investigators randomly assigned 6609 patients with an estimated glomerular filtration rate (eGFR, in mL/min/1.73 m2) of 20 to less than 45 or an eGFR of 45 to 90 with a urinary albumin-to-creatinine ratio (UACR) of at least 200 mg/g to receive empagliflozin (10 mg once daily) or matching placebo. Of these patients, 54% did not have diabetes.

During a median 2.0 years, a composite endpoint of CKD progression or death from cardiovascular causes occurred in 13.1% of the empagliflozin group and 16.9% of the placebo group, with the empagliflozin group experiencing a significant 28% decreased risk for the endpoint, William G. Herrington, MD, and Richard Haynes, DM, of the University of Oxford in the UK, and other members of the EMPA-KIDNEY

Collaborative Group reported. The investigators defined CKD progression as development of end-stage kidney disease, a sustained decrease in eGFR of 40% or more or an eGFR less than 10, or death from renal causes.

The beneficial effect of empagliflozin vs placebo was more pronounced among patients with diabetes. In this

endpoint associated with empaglifozin treatment: 36% compared with 27% in patients with an eGFR less than 30 and 22% for those with an eGFR of 30 or higher but less than 45.

The risk for all-cause hospitalization also was a significant 14% lower for the empagliflozin group, the team reported. Rates of serious adverse events were comparable.

“Among a wide range of patients with chronic kidney disease who were at risk for disease progression, empagliflozin therapy led to a lower risk of progression of kidney disease or death from cardiovascular causes than placebo,” the investigators concluded.

Anemia Tied to Dementia Risk in CKD

ANEMIA IS independently associated with an increased risk for dementia among patients with new-onset chronic kidney disease (CKD), according to researchers.

group, empagliflozin was significantly associated with a 36% decreased risk for CKD progression or death from cardiovascular causes. Among patients without diabetes, empagliflozin was significantly associated with an 18% reduced risk for this combined endpoint.

Stratified by eGFR, patients with an eGFR of 45 or higher had the greatest reduction in risk of the combined

The authors noted that key strengths of the trial “were its large size and broad eligibility criteria, the high level of adherence to the trial regimen, and the almost complete follow-up of all patients.”

They also acknowledged limitations, such as the lower-than-expected number of cardiovascular events. This decreased the statistical power for assessment of secondary and tertiary cardiovascular outcomes. ■

No Need to Stop RAS Inhibitors in Advanced CKD

DISCONTINUING renin-angiotensin system (RAS) inhibitors in patients with advanced or progressing chronic kidney disease (CKD) does not result in a clinically relevant change in estimated glomerular filtration rate (eGFR) or difference in the rate of long-term decline in eGFR, investigators reported.

inhibitors or angiotensin receptor blockers in patients with advanced CKD may increase eGFR. In addition, current guidelines do not specifically address the use of RAS inhibitors in advanced CKD.

Sunil Bhandari, PhD, of Hull University Teaching Hospitals NHS Trust in Kingston upon Hull, UK, and colleagues conducted the multicenter, open-label STOP-ACEi trial to determine whether discontinuation of these agents could slow progression of CKD in patients with stage 4-5 CKD. They randomly assigned patients to either discontinue or to continue RAS inhibitors. The eGFR at 3 years was the primary study outcome. The study enrolled 411 patients.

presentation. End-stage kidney disease or initiation of renal replacement therapy occurred in 128 patients (62%) in the discontinuation group and 115 patients (56%) in the continuation group. None of these between-group differences were statistically significant.

“If indicated for the treatment of hypertension, proteinuria or cardiovascular disease, [RAS inhibitors] should not be stopped just because eGFR is low,” Dr Bhandari and colleagues concluded.

In a study that included 444,474 US veterans aged 65 years or older with new-onset CKD, patients with mild anemia and moderate or severe anemia had a significant 12% and 23% increased risk for dementia, respectively, compared with those who did not have anemia after adjusting for potential confounders, Alain Koyama, ScD, of the Centers for Disease Control and Prevention in Atlanta, Georgia, and colleagues reported in a poster presentation. The investigators adjusted for demographics and baseline clinical characteristics.

The incidence of dementia per 1000 patient-years was 35.9 for patients without anemia compared with 46.1 and 52.7 for those with mild anemia and moderate or severe anemia, respectively.

Dr Koyama’s team defined newonset CKD as an eGFR less than 60 mL/min/1.73 m2 for more than 3 months. The study population was free of dementia and end-stage kidney disease at baseline. The investigators defined mild anemia as a hemoglobin level of 11.0-11.9 g/dL in women and 11.0-12.9 g/dL in men and moderate or severe anemia as a hemoglobin level less than 11.0 g/dL. They identified new-onset dementia during follow-up using ICD-9/10 codes in claims from the Veterans Health Administration and Centers for Medicare & Medicaid Services.

Study findings were published concomitantly in New England Journal of Medicine.

A previous small observational study suggested that discontinuation of ACE

At 3 years, the least-squares mean eGFR was 12.6 mL/min/1.73 m2 in the discontinuation group and 13.3 mL/ min/1.73 m2 in the continuation group, Dr Bhandari’s team reported in a poster

The trial had insufficient power to study the effect of RAS inhibitor discontinuation on cardiovascular events and death, they noted. “However, because our findings are consistent with a lack of advantage for such discontinuation with respect to kidney function, there is little rationale to conduct a larger randomized trial to investigate cardiovascular safety,” they wrote in their journal article. ■

Previous studies have demonstrated an association between newly diagnosed anemia and dementia in patients in a general population and an association between anemia and an increased risk for dementia among patients with newly diagnosed type 2 diabetes. ■

Protective effect observed in patients with and without diabetes

American Society of Nephrology’s Kidney Week 2022, Orlando, Florida

Researchers also report a reduced risk for all-cause hospitalization.

Discontinuing vs continuing therapy had no significant effect on eGFR.

Nephrologists Lag in SGLT2i Prescribing

NEPHROLOGISTS’ USE of sodiumglucose cotransporter-2 inhibitors (SGLT2is) has risen substantially from 2015 to 2022, but they account for only a small fraction of prescriptions for the drugs, according to investigators.

Studies have demonstrated that SGLT2is substantially slow kidney function decline and decrease cardiorenal mortality. Clinical guidelines recommend these drugs as first-line therapies for most patients with CKD. Kidney Disease: Improving Global Outcomes (KDIGO) guidelines recommend using SGLT2 inhibitors for all patients with diabetic CKD.

Using the IQVIA National Prescription Audit, which captures about 93% of US retail prescription dispensing activity, Rishav Adhikari, MD, and colleagues at Johns Hopkins University School of Medicine in Baltimore, Maryland, analyzed SGLT2i prescription data from January 2015 to April 2022. During that time,

nephrologists’ monthly prescriptions for SGLT2is increased 35-fold, but still accounted for only 1.26% of total prescriptions in the final 12 months of the study period (May 2021 to April 2022) compared with 56% of primary care physicians, Dr Adhikari and colleagues reported in a poster presentation.

accounted for 316, 28, and 18 prescriptions per physician, respectively.

“Nephrologists must recognize current gaps in CKD management, particularly the underutilization within their field of evidence-based [SGLT2is], and should adjust clinical practices to close those gaps,” the authors concluded.

After dapagliflozin received a Food and Drug Administration approved indication for CKD, nephrologists have predominantly used that drug. They prescribed it more frequently than nonnephrologists (52% vs 28% of prescriptions), Dr Adhikari’s team reported.

In the final 12 months, endocrinologists accounted for 11-fold more SGLT2i prescriptions than nephrologists.

On a per-physician basis, nephrologists accounted for 21 prescriptions per physician in the final 12 months of the study period, whereas endocrinologists, primary care physicians, and cardiologists

Overall, use of SGLT2 inhibitors among nephrologists “notably accelerated following publication of favorable renal outcomes trials,” the investigators wrote.

“Deploying [SGLT2is] will require a focused and coordinated effort across the medical specialties that manage patients with cardiorenal diseases, including an enhanced role for the nephrologist,” they concluded.

AKI Common After Radical Cystectomy

ACUTE KIDNEY injury (AKI) and acute kidney disease (AKD) are common complications of radical cystectomy for muscle-invasive bladder cancer (MIBC), according to the findings of a recent study.

Investigators identified hypertension at baseline as a unique risk factor for these complications.

Francesco Trevisani, MD, of IRCCS Ospedale San Raffaele in Milan, Italy, and colleagues studied 280 patients (258 men and 22 women) who under-

went radical cystectomy for MIBC. AKI and AKD developed in 51.4% and 37.5% of patients, respectively, the investigators reported in a poster presentation. Both AKI and AKD occurred in 23.6% of patients, whereas 13.9% of patients experienced AKD, but not AKI. Surgical approach was not a factor.

Baseline hypertension was present in 63% of patients with AKI and AKD compared with 46% of patients without AKI and AKD, according to the investigators.

The authors concluded that AKI and AKD are frequent side effects from radical cystectomy for MIBC and require the nephrological counseling immediately after the procedure to monitor for onset of both complications.

Of the 280 patients, 209 (75%) underwent open surgery and 71 (25%) had robotic surgery, and 44 (16%) received neoadjuvant chemotherapy. In addition, 35 patients (12%) had type 2 diabetes, 153 (55%) had hypertension, and 18 (6.4%) had ischemic heart disease. ■

A separate study presented at the conference also found low prescribing of SGLT2is by nephrologists. Tripti Singh, MD, of the University of Wisconsin in Madison, and colleagues analyzed responses from 153 nephrologists who participated in an online survey. A minority of respondents (33.6%) said they prescribe SGLT2is to more than 50% of their patients who meet requirements for the drugs. The survey identified barriers to prescribing the drugs, the most common being the cost of the medications or high copays (34% of respondents), lack of experience or comfort in prescribing the drugs (29%), and lack of time and personnel to manage the side effects (11%).

Survey responses revealed that professional guidelines (29%), readily available medical knowledge through social media (26%), and participation in professional conferences (18%) were the mechanisms that have helped the most in prescribing SGLT2is. ■

Bicarbonate Therapy May Up CKD Risk

PCa Treatment More Likely in Dialysis Patients

PATIENTS on dialysis are more likely to be treated for prostate cancer versus non-dialysis patients and kidney transplant recipients, new findings suggest.

Using the Surveillance, Epidemiology and End Results (SEER)-Medicare database, Nagaraju Sarabu, MD, of University Hospitals in Cleveland, Ohio, and colleagues studied 272

men with low-risk prostate cancer: 42 patients on dialysis, 20 kidney transplant recipients, and 210 patients without end-stage kidney disease (ESKD).

The non-ESKD group had significant 73% decreased odds of curative treatment compared with the dialysis group, the investigators reported in a poster presentation. None of the

kidney transplant recipients died from prostate cancer.

“Dialysis patients, who are more likely to die of other causes, are paradoxically more likely to be treated for low-risk prostate cancer,” the authors concluded. “Active surveillance should be performed in this population, and should not preclude transplant eligibility.” ■

BICARBONATE therapy may increase the risk for incident chronic kidney disease (CKD) and death among US veterans with normal kidney function. The finding is from a study of a national cohort of 238,313 US veterans with an estimated glomerular filtration rate of 60 mL/min/1.73 m2 or higher and urinary albumin creatinine ratio less than 30 mg/g at baseline. Of these, 2992 were incident bicarbonate users. In a propensity scorematched cohort of 5968 patients, bicarbonate therapy was significantly associated with a 2.8- and 2.3-fold increased risk for incident CKD and death, respectively, Hanwen Wang, MD, of Tibor Rubin VA Medical Center in Long Beach, California, and colleagues reported. ■

Cost is a barrier to prescribing the medications, a study shows.

Incremental Hemodialysis Is Not Associated With Higher Death Risk

THE RISK FOR DEATH is comparable between incremental and conventional hemodialysis (HD) in patients with sufficient residual kidney function (RKF), investigators report.

Emma Caton, MSc, of the University of Hertfordshire in the United Kingdom, and colleagues performed a systematic review of 22 cohort studies, 2 randomized controlled trials (RCTs), 1 non-randomized controlled trial, and 1 pre-post study involving a total of 101,476 adults receiving HD. Included studies had a low to moderate risk of bias.

In a meta-analysis of 18 studies, mortality risk did not differ significantly between groups receiving incremental HD (1-2 sessions per week) and conventional HD (at least 3 sessions per week), the investigators reported in Nephrology Dialysis Transplantation.

Clinical circumstances guided the decision to initiate incremental HD in 18 studies, whereas socioeconomic pressures forced the decision in 8 studies. Mortality risk was nonetheless comparable after sensitivity analyses excluding patients receiving incremental HD due to factors such as lack of

income, insurance, or proximity to a dialysis center.

According to data from the 2 RCTs, incremental HD also is significantly associated with a 69% reduced risk of hospitalization compared with conventional HD, the investigators reported.

alternative to standard care in patients with sufficient RKF.”

Additional randomized controlled trials are still needed to determine the safety and efficacy of incremental vs conventional HD.

Budesonide May Ease IgA Nephropathy

Too few studies assessed vascular access complications, fluid overload, hyperkalemia, acidosis, loss of residual kidney function, symptom scores, and quality of life to make definitive conclusions. Four studies estimated the costs of both regimens and suggested that incremental HD may be cost-saving.

According to Caton’s team, “the findings from this review lend support to the safety of incremental HD as a treatment for ESKD and highlight the potential for this method to be implemented as an

Among the studies considered in the review was the first prospective randomized trial of incremental versus conventional HD. The results, published in Kidney International in 2021, demonstrated that incremental HD appears safe and cost-saving in patients with adequate RKF. The trial, by Enric Vilar of Lister Hospital, East and North Herts NHS Trust, Hertfordshire, UK, and colleagues, included 55 incident HD patients with a urea clearance of 3 mL/min/1.73 m 2 or higher. They randomly assigned patients to conventional or incremental HD schedules for 12 months. Incremental HD involved twice-weekly sessions; standard HD consisted of thrice-weekly sessions. The groups had similar RKF at baseline. At 6 months, the groups did not differ significantly with respect to urea clearance and body surface area-corrected glomerular filtration rate slope. ■

Vaginal Delivery Ups Risk for SUI, POP Surgery

WOMEN HAVE the highest risks for stress urinary incontinence (SUI) surgery and pelvic organ prolapse (POP) surgery after their first vaginal childbirth, according to new study findings presented at the International Continence Society’s 2022 annual meeting (ICS 2022) in Vienna, Austria.

Using the 2010-2017 Swedish National Quality Register of Gynecological Surgery, investigators identified 59,415 women aged 45 years and older who had SUI or POP surgery. The vast majority of women who underwent SUI surgery (93.1%) had 1 or more vaginal deliveries, whereas just 2.6% had C-sections, and 4.3% were never pregnant. POP surgery showed a similar pattern: 97.8% of patients had 1 or more vaginal deliveries, whereas 0.4% had C-sections, and 1.9% were never pregnant.

The vaginal delivery group had a significant 22% and 28% higher risk for SUI and POP surgery, respectively, compared with the age-matched general female

population, Jennie Larsudd-Kåverud, MD, of Gothenberg Continence Research Center at the University of Gothenberg in Sweden reported on behalf of her team. In contrast, the never-pregnant and C-section groups had significant 69% and 74% lower risks for SUI surgery and 26% and 99.6% lower risks for POP surgery, respectively.

In absolute terms, the risk for POP surgery was highest in the vaginal delivery group (2.1%) and lowest in the C-section group (0.09%) — a 23-fold difference.

The first vaginal delivery carried the highest absolute risks: a 6.0-fold increased risk for POP surgery and a 3.0-fold risk of SUI surgery. Compared with the first vaginal delivery, the second vaginal birth carried a quarter of the risk for POP surgery and a tenth of the risk for SUI surgery.

“The result of the present study did not support the assumption that one or more pregnancies in themselves may cause long-term effects on the pelvic

floor leading to POP and SUI surgery,” Dr Larsudd-Kåverud concluded in a study abstract.

Previous studies have demonstrated an association between vaginal deliveries and an increased risk for pelvic floor disorders. For example, a study of 1528 women showed that, compared with spontaneous vaginal deliveries, C-sections were associated with a significant 54%, 49%, and 72% lower risk for SUI, overactive bladder, and POP, respectively, in adjusted analyses, whereas operative vaginal delivery was associated with significant 75% and 88% higher risk for anal incontinence and POP, respectively, Joan L. Blomquist, MD, of the Greater Baltimore Medical Center in Baltimore, Maryland, and colleagues reported in a 2018 paper published in JAMA. The study population included 778 women who had C-sections, 565 who had spontaneous vaginal deliveries, and 185 who had operative vaginal deliveries. ■

BUDESONSIDE IMPROVES the urinary protein-to-creatinine ratio (UPCR) and maintains estimated glomerular filtration rate (eGFR) in adult patients with IgA nephropathy (IgAN), according to interim results from a phase 3 randomized clinical trial (RCT).

“This is the first phase 3 RCT to show treatment benefits of this magnitude with a drug that we postulate may target the underlying pathophysiology of IgAN,” Brad H. Rovin, MD, of Ohio State University Wexner Medical Center in Columbus, and colleagues reported in Kidney International.

In Part A of the double-blind NefIgArd trial, researchers randomly assigned 199 patients with IgAN and persistent proteinuria despite stable, optimized renin angiotensin system blockade to budesonide (16 mg/d) or placebo for 9 months. At baseline, median UPCR was 1.26 g/g and median proteinuria was 2.26 g/24 hours (58% had proteinuria of 2 g or more in 24 hours). Median eGFR was 55 mL/min/1.73 m2

The budesonide formulation was Nefecon, a corticosteroid hypothesized to target mucosal B-cells in the ileum, including the Peyer’s patches, which are responsible for the production of galactose-deficient IgA1 antibodies (Gd-Ag1) causing IgAN.

At 9 and 12 months, 24-hour UPCR was a significant 27% and 48% lower, respectively, in the budesonide vs placebo group, Dr Rovin’s reported. In addition, eGFR at 9 months was preserved in the budesonide group with a decrease from baseline of 0.17 vs 4.04 mL/min/1.73 m2 in the placebo group.

Treatment-emergent adverse events (TEAEs) occurred in 86.6% of the budesonide group and 73.0% of the placebo group. Most TEAEs were mild to moderate (1% severe) and reversible, the investigators reported. The most common TEAEs in the budesonide group were hypertension, peripheral edema, muscle spasms, and acne. Infection occurred in 39.2% of the budesonide and 41.0% of the placebo group. ■

This approach could lower costs compared with conventional HD, data suggest

Meta-analysis also revealed a lower risk of hospitalization vs conventional HD

More PSA Screening Tied to Lower mPCa Incidence

BY JOHN SCHIESZER

IN A LARGE STUDY of men receiving care at Veterans Health Administration (VHA) medical centers, investigators found that facilities with higher PSA screening rates had lower subsequent rates of metastatic prostate cancer (mPCa).

Over the past 12 years, conflicting data and changes in clinical practice guidelines have led to a drop in PSA screening rates across the country, the investigators noted. PSA screening rates declined in the VHA system from 47% in 2005 to 37% in 2019, with declines observed across all ages and races. The incidence of mPCa rose from 5.2 cases per 100,000 men in 2005 to 7.9 per 100,000 in 2019.

Each 10% increase in PSA screening rate was significantly associated with a 9% decrease in the incidence of metastatic prostate cancer 5 years later, the investigators reported. Each 10%

generalize to men outside the national VA health system,” said Roman Gulati, MS, of the Fred Hutchinson Cancer Research Center in Seattle, Washington, where he is a designer, developer, and analyst of statistical models for investigating population impacts of national clinical practice

patterns and cancer control policies. “Although the results are unsurprising, studies like this one are invaluable for understanding real-world trends in new cancer diagnoses,”

Douglas M. Dahl, MD, Chief of the Division of Urologic Oncology at Massachusetts General Hospital

Cancer Center and Associate Professor of Surgery at Harvard Medical School, both in Boston, said the VHA population is a good way to capture evidence across a national health system in the United States. The results are consistent with other data showing the detrimental impact of the US Preventive

increase in long-term non-screening rates (the percentage of patients who missed screenings 3 years in a row) was significantly associated with an 11% increase in the incidence of metastatic prostate cancer 5 years later.

Alex K. Bryant, MD, a radiation oncology resident physician at the University Michigan Rogel Cancer Center in Ann Arbor, and colleagues reported study findings at the 2022 American Society for Radiation Oncology annual meeting in San Antonio, Texas. Study results were published concomitantly in JAMA Oncology.

The new data can be used to inform shared decision making about the potential benefits of PSA screening in men who wish to reduce their risk of metastatic prostate cancer, Dr Bryant and colleagues concluded.

Dr Bryant and colleagues analyzed data from all men aged 40 years or older receiving care at 128 facilities in the VHA health system from January 1, 2005 to December 31, 2019. The cohort grew from 4,678,412 men in 2005 to 5,371,701 men in 2019.

“The study appears to be carefully done, and the main takeaways likely

Each 10% increase in PSA screening was associated with a 9% lower mPCa rate.

PSA screening

Services Task Force (USPSTF) 2012 grade D recommendation against PSA screening.

“Metastatic [prostate cancer] rates have been on the rise since then after decades of progress,” Dr Dahl said. “I think a new and really important finding is the 3-year gap in screening

also being tied to increased metastatic rate. This is so relevant to the COVIDrelated disruptions in early detection which will also likely show downstream negative effects. We are seeing so many men with aggressive tumors who unfortunately did not get routine medical care due to the pandemic.”

While the USPSTF changed back to a grade C recommendation, Dr Dahl said significant damage occurred. “Much of

the foundation for recommendations against screening are no longer valid,” Dr Dahl said. “It used to be that any abnormal PSA automatically meant a biopsy. Now, we have MRI done prior to biopsy, which results in differentiating very well between those who need biopsy and those who don’t.”

The use of transperineal biopsy has nearly eliminated the risk of serious infections or bleeding due to biopsy,

according to Dr Dahl. With MRI guidance, he said biopsies are substantially more accurate in making a diagnosis so appropriate treatment or surveillance can be tailored to the situation. “It used to be any diagnosis of prostate cancer automatically meant aggressive treatment,” he said. “Now, a large cohort of our patients are monitored instead of having treatment. This is widely accepted and found to be safe.” ■

Newer Drugs for Nonmetastatic CRPC Underused

ANDROGEN deprivation therapy (ADT) combined with novel hormone therapies (NHTs) improves metastasisfree and overall survival among men with high-risk nonmetastatic castrationresistant prostate cancer (nmCRPC), but these regimens are underused in this patient population, according to

study findings presented at the European Society for Medical Oncology’s 2022 Congress in Paris, France.

The findings are from a retrospective study of 2007-2020 data from the Optum electronic health records database. Sumati Gupta, MD, of Huntsman Cancer Institute at the University

of Utah in Salt Lake City, and colleagues studied 1572 men with highrisk nmCRPC. As first-line treatment, 48.2% received ADT only, 32.9% received ADT plus first-generation nonsteroidal antiandrogens (NSAAs), 8.8% received ADT plus NHTs, and 10.1% received other regimens. As of 2018-

2020, only 21% of patients received ADT plus NHTs (including those with a PSA doubling time of 4 months or less), whereas 44.5% received ADT alone and 26.2% received ADT plus NSAAs. Patients with PSA doubling time of 10 months or less are at high risk for metastatic disease. ■

PSMA Status of CTCs Could Guide mCRPC Therapy

BY JOHN SCHIESZER

PROSTATE - SPECIFIC membrane antigen (PSMA) expression on circulating tumor cells (CTCs) in men with metastatic castration-resistant prostate cancer (mCRPC) is heterogeneous and increases upon disease progression during treatment with abiraterone or

enzalutamide, investigators reported at the European Society for Medical Oncology’s 2022 Congress in Paris.

In a retrospective analysis of 97 men treated with abiraterone or enzalutamide in the multicenter PROPHECY trial, Andrew J. Armstrong, MD, of the Duke Cancer Institute Center

for Prostate and Urologic Cancers in Durham, North Carolina, and colleagues demonstrated that prostate cancer CTC PSMA status provides useful prognostic information that informs therapeutic decision-making.

“Given that PSMA-negative disease is also quite aggressive, it is important to

understand which patients have significant disease that lacks the target both prior to treatment and during treatment in order to optimize care delivery and predict resistance and also to develop better therapies for these men,” Dr Armstrong said. “In addition, men with more intense and homogeneous

PSMA expression by PSMA PET/CT have better outcomes with PSMAdirected radioligand therapy, and if we can better identify these men through a liquid biopsy, this would be a significant advance in facilitating precision medicine for men with advanced prostate cancer.”

In the current study, the overall CTC prevalence prior to treatment with abiraterone or enzalutamide in the

mCRPC setting was 80%, with 55% of patients harboring PSMA-positive CTCs, Dr Armstrong’s team reported in a poster presentation. On progression during treatment, CTCs were present in 88% of patients, with PSMA expression detected in 68% of them. In an analysis limited to men with PSMApositive CTC cells and whose disease progressed despite treatment, 34% had PSMA expression on more than

50% of their CTCs at progression compared with 14% at baseline, according to the investigators. Thus, PSMA CTC expression is fairly uniform in some men and heterogeneous in others, and some lacked PSMA detection despite having many detectable CTCs. After adjusting for multiple variables, PSMA positivity at the optimal threshold of 2 or more CTCs per mL was associated with a significant 3-fold increased risk

for death and a nonsignificant 2.3-fold increased risk for radiographic progression compared with PSMA negativity (fewer than 2 CTCs per mL).

For the study, Dr Armstrong and colleagues used a novel liquid biopsy assay developed by Epic Sciences. The investigators explained that the assay analyzes cellular parameters such as PSMA protein expression and cell morphology to differentiate candidate CTCs from surrounding white blood cells.

“This is really the first study to evaluate clinical outcomes of a PSMA-CTC assay in the context of potent [androgen receptor] therapy and mCRPC patients, and we anticipate that this PSMA liquid biopsy could be helpful to enable precision medicine approaches going forward, and will lead to planned trials in the context of PSMA targeted therapies,” Dr Armstrong said.

He added, “This assay is non-invasive and could be repeated over time to track response and update prognosis as well.”

Oncologists acknowledged the potentially important role that prostate cancer CTC PSMA status could have in treating patients. Klaus Pantel, MD, of the Department of Tumor Biology at University Medical Center HamburgEppendorf in Hamburg, Germany, said the findings are a significant advance toward better understanding when best to adopt PSMA-targeted therapies.

“Our group published already about the heterogeneity of PSMA expression on CTCs some years ago, but we did not include clinical follow-up information,” Dr Pantel said. “It is important to know for urologists and radiologists that PSMA expression is heterogeneous because PSMA is being used as a diagnostic and therapeutic target in prostate cancer.”

Howard Scher, MD, Chief of the Genitourinary Oncology Service within the Sidney Kimmel Center for Urologic and Prostate Cancers at Memorial Sloan Kettering Cancer Center in New York, agreed that the latest findings are an important contribution. “The results suggest that the detection of PSMA-expressing circulating tumor cells predicts for sensitivity to PSMA-directed radionuclide therapy,” Dr Scher said. ■

Investigators used a novel liquid biopsy assay that analyzes cellular parameters.

Shift in Metastatic Prostate Cancer Care Advocated

More aggressive treatment at an earlier stage is needed, according to researchers

BY JODY A. CHARNOW

Novel therapies that have entered clinical practice over the past 12 years have extended the lives of men with metastatic prostate cancer, population-based studies show. Still, survival gains have been modest, and the prognosis for men with metastatic prostate cancer remains poor. Investigators involved in prostate cancer research say longer survival is possible, but the management approach needs to change. Based on insight gained from ongoing research and the availability of more precise imaging techniques, they believe the path forward should involve earlier use of aggressive treatment.

“I am convinced that treating early and hard is better than late and less,” said urologic oncologist Judd W. Moul, MD, the James H. Semans Distinguished Professor of Urologic Surgery at Duke University School of Medicine in Durham, North Carolina, who has been extensively involved with clinical trials of prostate cancer therapies. “Some doctors still ‘hold the good stuff in their back pocket’ and avoid or delay the most effective options up front.”

“Starting multiple therapies earlier in the disease course seems to provide the most benefit,” said prostate cancer investigator Jonathan E. Shoag, MD, Assistant Professor of Urology at Case Western Reserve University School of Medicine in Cleveland, Ohio.

Despite all of the scientific advancements, metastatic prostate cancer “is still a bad disease,” Dr Shoag said. “The goal should be preventing cancer from becoming metastatic in the first place. We can do this by screening, diagnosing, and intervening in the disease course earlier.”

Advanced molecular imaging, such as positron emission tomography (PET),

should be used to identify metastasis as early as possible, before it spreads to distant anatomic sites, according to investigators. Potent treatments should be considered at this stage. Physicians also should try to delay development of both metastasis and castration-resistant prostate cancer (CRPC), which clinical trial data suggest is possible.

Earlier identification and treatment of metastatic CRPC (mCRPC) is key, Dr Moul said, adding that targeted therapy based on the molecular characteristics of the patient or tumor or both continues to lead to advancements in treatment. “I remain optimistic that we will continue to achieve better survivals with targeted combos and with further molecular discoveries,” Dr Moul said.

Advances in PET imaging, such as PSMA (prostate-specific membrane antigen) PET, that improve detection of metastases compared with traditional bone scans and computed tomography

(CT) and magnetic resonance imaging (MRI) will play an increasingly important role, Dr Moul said. “As we all know, traditional bone scans and CT/MRI miss a lot of early metastatic disease,” he said. “Novel functional imaging with PET is opening a whole new era. At this point, I routinely order PSMA PET to work up biochemical recurrence as well as in nonmetastatic CRPC and in newly diagnosed men with very high risk disease.”

Radiation oncologist Amar U. Kishan, MD, Chief of the Genitourinary Oncology Service and Vice Chair of Clinical and Translational Research for the Department of Radiation Oncology at the University of California, Los Angeles, also embraces PSMA PET. “I believe that PSMA scans should be routine as part of the diagnostic workup for patients with recurrent disease after primary therapy, and even for those with previous recurrences who have a second recurrence and those who might have

progression on therapy,” Dr Kishan said. “While there are certain rarer types of prostate cancer that might not be detectable on PSMA PET/CT, PSMA PET has been shown to greatly increase sensitivity and even specificity for disease over older forms of imaging.”

Urologist Stephen J. Freedland, MD, Director of the Center for Integrated Research in Cancer and Lifestyle at Cedars-Sinai Medical Center in Los Angeles, California, observed that the aggressive management of metastatic disease imaged with conventional modalities (bone scan or CT) has pushed survival out to 5 or 6 years. “Finding cancers even earlier will create a leadtime bias and thus survival from that alone will be longer,” said Dr Freedland, who also is Co-Director of CedarsSinai’s Cancer Genetics and Prevention Program. “However, whether the same therapies applied to PET-only metastases extends survival even longer is unknown.”

For now, the most promising treatments are the novel hormonal therapies, according to Dr Freedland. “They have shown remarkable benefits across multiple disease states, including in castration-sensitive disease to prevent development of CRPC,” he said, adding that, relatively speaking, the drugs are well tolerated despite their side effects.

“For sure, the future will include targeted molecular therapies,” Dr Freedland said. “We are there now with PARP inhibitors for some patients.”

The Expanding Armamentarium

Patients with metastatic prostate cancer in the United States have benefited from an expanding armamentarium of novel therapies, especially since 2010, when the

A scintigram showing the pelvis of a man whose prostate cancer has metastasized.

Food and Drug Administration (FDA) approved cabazitaxel for mCRPC and sipuleucel-T, the first therapeutic cancer vaccine, for asymptomatic or minimally symptomatic mCRPC. These approvals were followed by the approval of abiraterone in 2011 and enzalutamide in 2012 for treating mCRPC. The following year, FDA approved the radiopharmaceutical radium-223 for the treatment of symptomatic bone metastases in CRPC. In 2018 and 2019, the FDA approved apalutamide and darolutamide, respectively, for treating nonmetastatic CRPC, but subsequently expanded the indication for these agents, as well as for abiraterone and enzalutamide, to include metastatic castration-sensitive prostate cancer (mCSPC). The FDA in 2022 approved lutetium-177 PSMA, another radiopharmaceutical, for treating patients with mCRPC and who have PET scans demonstrating PSMA.

Real-World Evidence

Real-world evidence shows that the newer agents are improving overall survival of men who have metastatic prostate cancer, a confirmation of clinical trial data. At the American Urological Association’s 2022 annual meeting, Dr Shoag and colleagues presented findings from their study of Surveillance, Epidemiology, and End Results (SEER) program data showing that men diagnosed after 2011 (the year the FDA approved abiraterone) had a significant 20% lower risk for all-cause mortality and 25% lower risk for prostate cancerspecific mortality, respectively, compared with those diagnosed from 2000 to 2008.1 In addition, an analysis of data from the electronic medical records of 2559 men with mCRPC showed that the median overall survival of patients who received at least 1 line of abiraterone, enzalutamide, docetaxel, cabazitaxel, sipuleucel-T, or radium-223 had a significantly longer median overall survival compared with those who did not (23.7 vs 10.1 months), investigators reported in Clinical Genitourinary Cancer 2 And a Norwegian study published in Prostate Cancer & Prostatic Diseases demonstrated that the median overall survival of men with mCRPC increased from 2.3 years in 2004-2009 to 3.3 years in 20152018. The 3-year overall survival rate increased to 51% from 41% between those time points.3

Overall survival also improved among men with mCSPC, according to study findings presented at the European Society for Medical Oncology 2022 Congress. Daniel J. George, MD, of Duke University Medical Center in

Durham, North Carolina, and colleagues studied 39,292 men with mCSPC (33,641 with Medicare coverage and 5651 receiving care at Veteran’s Affairs [VA] medical facilities). Compared with Medicare and VA patients treated during 2010 to 2011, Medicare patients treated from 2015 to 2018 and VA patients treated from 2015 to 2019 had a significant 13% and 15% lower risk for death, respectively, the investigators reported.4

Despite the positive trend, however, improvements in survival have been marginal, according to the findings of a population-based study published in Cancer Medicine 5 In an analysis of SEER data, a team led by Isaac Yi Kim, MD, of Rutgers Cancer Institute of New Jersey in New Brunswick, found that the median survival time increased from 24 months for men diagnosed with metastatic prostate cancer from 2000 to 2003 to 28 months for those diagnosed with it from 2010 to 2016.

“Although we have made considerable headway in the options available to patients with advanced prostate cancer, we still are likely seeing advancements provide additional months, rather than years, in terms of overall survival,” said prostate cancer investigator Christopher P. Filson, MD, Associate Professor of Urology at Emory University School of Medicine in Atlanta, Georgia, where he is a member of the Cancer Prevention and Control research program at the Winship Cancer Institute. “The median survival for men presenting with metastatic disease is still around 3 years, so there is still room for improvement before we consider this a chronic disease state for most advanced prostate cancer patients.”

Cure In That State ‘Not Possible’

Dr Filson also observed, “As of right now there is a limit to what we can achieve with medications and systemic therapies for patients with metastatic prostate cancer. To date, cure in that state is not possible. However, I remain hopeful that continued scientific advancements can help reach the goal of eventually offering curative options for patients with metastatic prostate cancer. For now, the best path to minimizing the detrimental effects of prostate cancer is to promote early detection and judiciously offering curative treatment to those who need it most.”

Still, the growing list of effective treatments is good news given that metastatic prostate cancer is on the rise in the United States. In a study of SEER data, Mihir M. Desai, MD, MPH, of University of Southern California’s Keck

School of Medicine in Los Angeles, and colleagues found no statistically significant increase in the incidence of metastatic prostate cancer from 2004 to 2010 among men aged 45 to 75 years, but the incidence increased 41% from 2010 to 2018, according to findings published in JAMA Network Open 6 Among men aged 75 years or older, the incidence declined during 2004 through 2011, but rose 43% afterward, according to the investigators. They pointed out that the upward trend occurred following US Preventive Services Task Force recommendations against routine PSA screening, first for men older than 75 years in 2008 and then for all men in 2012. Based on separate analysis of SEER data, investigators at the National Cancer Institute led by Lisa Gallicchio, PhD, project that the number men living with metastatic prostate cancer in the United States will rise to 156,812 by January 1, 2025, up from an estimated 120,368 men on January 1, 2018, according to a recent report in the Journal of the National Cancer Institute 7

Prostate cancer care already is moving toward earlier use of newer agents, as the approvals of abiraterone, enzalutamide, apalutamide, and darolutamide for use in mCSPC suggest. Neal D. Shore, MD, and collaborators tested the use of enzalutamide in patients on active surveillance for localized prostate cancer. Compared with patients undergoing active surveillance alone, those who also receive enzalutamide experienced significant 46% lower odds of prostate cancer progression and 29% lower odds of PSA progression, the investigators reported in JAMA Oncology. The enzalutamide arm also was 3.5 times more likely to have a negative biopsy result.8

Dr Moul observed that physicians are underusing effective therapies for men

with mCSPC. Despite having 5 therapeutic agents (docetaxel, abiraterone, apalutamide, darolutamide and enzalutamide) that markedly improve survival over androgen deprivation therapy (ADT) alone in men with mCSPC, “too many men in 2022 are still getting ADT alone,” Dr Moul said, adding that urologists need to recognize that ADT alone is substandard care for most men with mCSPC.

Transformation into a Chronic Illness?

Adam B. Weiner, MD, a urologic oncology fellow at the University of California, Los Angeles, said recent evidence suggests that investigators are making strides in turning metastatic prostate cancer into a chronic illness.

Dr Weiner pointed to the ARASENS trial, which examined the effect of ADT plus docetaxel, with or without darolutamide, on survival in men with mCSPC. At the end of follow-up, median survival was over 4 years in the men who did not receive darolutamide but not reached in the men who received the drug. In addition, the median time to castration resistance was 19 months among the men who did not receive darolutamide, but not reached in the darolutamide group.

“I think we still have a lot to learn about treatments for metastatic prostate cancer, and I think there is still room to grow,” Dr Weiner said. “First, we will still start to see the benefit of more targeted therapies for individual patients. We’ll continue to see newer agents targeting patients with specific susceptibilities based on genomic alterations or certain gene expression patterns. We will also continue to learn about the optimal ordering of treatments for patients who receive more than 1 line of

medication for castration-resistant prostate cancer. I also think the treatments we are optimizing for men with hormonesensitive prostate cancer will continue to delay the onset of castration resistance.”

“Triplet therapy” in the form of ADT, docetaxel, and an androgen receptor antagonist “is the most interesting strategy right now,” Dr Weiner said, adding this approach would be particularly bene cial for patients with a high-volume burden of metastatic cancer.

The ARASENS trial showed signi cant improvement in overall survival when darolutamide was added to docetaxel and ADT and delayed the need for additional treatments. For patients with low-volume metastatic prostate cancer, there is no direct evidence to support one treatment over another at this point, he said.

An important consideration, he said, is the use of androgen receptor antagonists in patients with high-risk nonmetastatic prostate cancer. Moving up the use of these agents can delay onset of metastatic disease, as demonstrated in an analysis of data from the STAMPEDE trial. Patients with high-risk nonmetastatic prostate cancer who received enzalutamide in addition to abiraterone plus prednisolone had superior metastasisfree survival at 6 years compared with those who did not (82% vs 69%).

Upfront Chemotherapy

Some research suggests that there may be a place for upfront chemotherapy. Dr Weiner led a real-world study comparing upfront chemotherapy in patients with de novo mCSPC (within 4 months of diagnosis) with a control group of patients who received no chemotherapy or chemotherapy later than 12 months after diagnosis. The median follow-up duration was 23 months. The median overall survival was signi cantly higher in the upfront chemotherapy group compared with the control arm (35.7 vs 32.5 months), which corresponded to a signi cant 22% lower risk for death, Dr Weiner’s team reported in Prostate Cancer & Prostatic Diseases 9

In a small real-world study, Oliver Sartor, MD, of Tulane University School of Medicine in New Orleans, Louisiana, and collaborators examined the use of lutetium-177 PSMA following radium-223 for bone-metastatic CRPC.

Patients received radium-223 (an alpha particle emitter) for a median of 6 injections and subsequent lutetium-177 PSMA (a beta particle emitter) for a median of 3.5 months. The median time between the treatments was 8 months. The median overall survival was 28 months from the start of radium-223 and 13.2 months from the start of lutetium-177 PSMA, the investigators reported in the Journal of Nuclear Medicine 10 The authors acknowledged that their small sample size precludes de nitive conclusions, but noted that their data, especially related to the duration of lutetium-177 PSMA, suggest that the use of this medication after radium-223 is feasible in a real-world setting.

Metastasis-Directed Therapy

Meanwhile, metastasis-directed therapy (MDT) is emerging as a treatment option for men with low-volume metastases, a trend helped along by highly sensitive and speci c molecular imaging techniques that can identify metastases early. In a prospective randomized phase 2 trial that enrolled men with oligometastatic prostate cancer, Piet Ost, MD, PhD, of Ghent University Hospital in Belgium, and colleagues demonstrated that the median ADT-free survival was 21 months for men who had MDT and 13 months for those who underwent surveillance, the investigators reported in the Journal of Clinical Oncology. 11 The study population had a median follow-up duration of 3 years.

Further, in an analysis of pooled data from the prospective STOMP and ORIOLE trials, a team led by Phuoc T. Tran, MD, PhD, of the University of Maryland School of Medicine in Baltimore, found that MDT was signicantly associated with a 56% reduction in the risk of disease progression in men with oligometastatic CSPC compared with observation after a median followup of 52 months. The median PFS — the study’s primary endpoint — was 11.9 months with MDT compared with 5.9 months with observation, Dr Tran and colleagues reported in the Journal of Clinical Oncology 12 Among patients with high-risk mutations, MDT was signi cantly associated with a 95% lower risk for disease progression, compared with observation, according to the

investigators. The median PFS was 7.5 months among MDT recipients compared with 2.8 months among those who underwent observation. Looking only at the MDT cohort, the investigators found that patients without high-risk mutations had a signi cantly longer median PFS compared with those who had these mutations (13.4 vs 7.5 months).

Treatment of Primary Tumor

Another approach that may prolong life is treatment of the primary prostate tumor. Stephen H. Culp, MD, of the University of Virginia in Charlottesville, and colleagues conducted a population-based study that included 8185 men with metastatic prostate cancer at diagnosis identi ed using SEER data: 7811 patients who received no surgery or radiation therapy (NSR), 245 who underwent RP, and 129 who received brachytherapy. The 5-year overall survival rates were signi cantly higher for the RP and brachytherapy groups (67.4% and 52.6%, respectively) compared with the NSR group (22.5%), according to data published in European Urology 13 The predicted disease-speci c survival rates also were higher for the RP and brachytherapy arms compared with the NSR group (75.8% and 61.3% vs 48.7%, respectively).

Treatments that prolong the lives of men with metastatic prostate cancer could mean increasing the likelihood of dying from something else. In a retrospective cohort study using 2000 to 2016 SEER data, investigators led by Omar Alhalabi, MD, of The University of Texas MD Anderson Cancer Center in Houston, found that among patients who died within 2 years of their diagnosis of metastatic prostate cancer, 79.0% died from their cancer while 15.7% died from noncancer causes such as cardiovascular disease and 5.3% died from other cancers, according to findings published in JAMA Network Open 14 But for those who died more than 5 years after their diagnosis, the proportion of patients dying from prostate cancer declined to 66.6% and the proportion of those who died from noncancer causes and from other cancers increased to 25.4% and 8.0%, respectively.

The American Cancer Society estimates that 34,500 men will die from prostate cancer in 2022. Although

metastatic prostate cancer remains incurable despite the best that state-ofthe-art medical science has to offer, the therapeutics and imaging techniques now available to physicians, as well as encouraging developments on the horizon, offer the promise of reducing that number in the years ahead. ■

REFERENCES

1. Omil-Lima DO, Wu X, Kent MA, et al. Effect of advances in treatment on a population-level of patients with metastatic prostate cancer. J Urol 2022;(suppl 5):e45. Presented at the American Urological Association 2022 annual meeting. Abstract PD03-10.

2. George DJ, Sartor O, Miller K, et al. Treatment patterns and outcomes in patients with metastatic castration-resistant prostate cancer in a real-world clinical practice setting in the United States. Clin Genitourin Cancer 2020;18(4):284-294. doi:10.1016/j.clgc.2019.12.019

3. Storås AH, Fosså SD, Ursin G, Andreassen BK. Survival trends for patients with primary metastatic prostate cancer before and after the introduction of new antitumor drugs. Prostate Cancer Prostatic Dis Published September 7, 2021. doi:10.1038/ s41391-021-00445-x

4. George DJ, Sandin R, Agarwal N, et al. Treatment patterns and overall survival (OS) in metastatic castration-sensitive prostate cancer (mCSPC) from 2010 to 2019. Poster presentation at the European Association for Medical Oncology 2022 Congress. Poster 1384P.

5. Kim IE, Jang TL, Kim S, et al. Marginal improvement in survival among patients diagnosed with metastatic prostate cancer in the second-line antiandrogen therapy era. Cancer Med. 2021;10:7909-7920. doi:10.1002/cam4.4074

6. Desai MM, Cacciamani GE, Gill K, et al. Trends in incidence of metastatic prostate cancer in the US. JAMA Netw Open. 2022;5(3):e222246. doi:10.1001/ jamanetworkopen.2022.22

7. Gallicchio L, Devasia TP, Tonorezos E, et al. Estimation of the numbers of individuals living with metastatic cancer in the United States. J Natl Cancer Inst. Published online August 22, 2022. doi:10.1093/ jnci/djac158

8. Shore ND, Renzulli J, Fleshner NE, et al. Active surveillance plus enzalutamide monotherapy vs active surveillance alone in patients with low-risk or intermediate-risk localized prostate cancer. JAMA Oncol. 2022;8(8):11281136. doi:10.1001/jamaoncol.2022.1641

9. Weiner AB, Ko OS, Li EV, et al. Survival following upfront chemotherapy for treatment-naïve metastatic prostate cancer: a real-world retrospective cohort study. Prostate Cancer Prostatic Dis. 2021;24:261-267. doi: 10.1038/s41391-020-00278-0

10. Sartor O, la Fourgère C, Essler M, et al. 177Lu-Prostatespeci c membrane antigen ligand after 223Ra treatment in men with bone-metastatic castrationresistant prostate cancer: Real-world clinical experience. J Nucl Med. 2022;63:410-414. doi:10.2967/ jnumed.121.262240

11. Ost P, Reynders D, Decaestecker K, et al. Surveillance or metastasis-directed therapy for oligometastatic prostate cancer recurrence: A prospective, randomized, multicenter phase II trial. J Clin Oncol. 2017;36:446-453. doi:10.1200/ JCO.2017.75.4853

12. Deek MP, van der Eecken, K, et al. Long-term outcomes and genetic predictors of response to metastasis-directed therapy versus observation in oligometastatic prostate cancer: Analysis of STOMP and ORIOLE trials. J Clin Oncol Published online August 24, 2022. doi:10.1200/JCO.22.00644

13. Culp SH, Schellhammer PF, Williams MB. Might men diagnosed with metastatic prostate cancer bene t from de nitive treatment of the primary tumor? A SEER-based study. Eur Urol 2014;65:1058-1066. doi:10.1016/j.eururo.2013.11.012

14. Elmehrath AO, A AM, Al-Husseini MJ, et al. Causes of death among patients with metastatic prostate cancer in the US from 2000 to 2016. JAMA Netw Open. 2021;4(8):e2119568. doi:10.1001/ jamanetworkopen.2021.19568

Post-RCC Treatment ESKD Risk Factors Identified

RADICAL nephrectomy (RN) for treatment of renal cell carcinoma is a risk factor for end-stage kidney disease (ESKD) during the first year after the procedure, investigators reported at the 2022 International Kidney Cancer Symposium: North America held in Austin, Texas.

During the 5 years after RCC diagnosis, male sex, advanced T-stage, diabetes, hypertension, and chronic kidney disease (CKD) stages 1-4 were significant risk factors, according to Sven Lundstam, MD, PhD, of Sahlgrenska University Hospital in Gothenburg, Sweden, and colleagues.

Using the National Swedish Kidney Cancer Registry, the investigators identified 9299 patients with RCC who did not have ESKD at the time of cancer diagnosis. ESKD developed in 215 patients. By comparison, 302 ESKD cases developed among 93,895 matched controls. The 10-year cumulative incidence of ESKD after RCC was 2.5%, half of which occurred within 2 years after RCC diagnosis, Dr Lundstam’s team reported.

not (29% vs 64%), according to the investigators. The ESKD group had a 2.4-fold higher risk for death than the group without ESKD.

The new finding differs from that of some previous studies. A nationwide population-based retrospective cohort study of 7670 patients who underwent

surgery for RCC in Taiwan revealed that patients who underwent RN have a higher incidence rate of ESKD compared with those who underwent PN (6.9 vs 5.5 cases per 1000 person-years), but the difference was not statistically significant in adjusted analyses, investigators reported in a 2015 article in PLOS One

In addition, in a propensity score matched-cohort of patients undergoing RN or PN for RCC (840 patients in each group) in the US, investigators found no significant difference between the groups in the risk for ESKD on multivariable analysis, according to a 2012 report in European Urology ■

Compared with controls, the RCC group had an 18-fold increased risk for ESKD in the first year after diagnosis and 7-fold increased risk during years 1 to 10.

On multivariable analysis, patients undergoing nephron-sparing approaches (partial nephrectomy [PN] or tumor ablation) had a significant 61% lower risk for ESKD compared with those undergoing RN during the first year of follow-up, Dr Lundstam and colleagues reported.

Within 5 years of RCC diagnosis, women had a significant 35% lower risk for ESKD compared with men. Patients with T2-T4 disease had a significant 40% increased risk for ESKD compared with those who had T1 disease. Patients with diabetes and hypertension had 89% and 87% increased risks for ESKD compared with patients who did not have these conditions. Patients with CKD stages 1-4 had a significant 15.5fold increased risk for ESKD compared with those who did not have CKD.

The patients with RCC who experienced ESKD had a significantly lower 5-year survival rate than those who did

Radical nephrectomy is associated with a greater likelihood of kidney failure.

Remdesivir Safe Despite Advanced CKD

THE ANTIVIRAL DRUG remdesivir is not currently recommended for use in patients with an estimated glomerular filtration rate (eGFR) less than 30 mL/ min/1.73 m2 due to concerns of excipient accumulation. Preliminary study findings indicate, however, that remdesivir can be safely administered to patients with advanced chronic kidney disease (CKD) who contract COVID-19.

In the Canadian Treatments for COVID-19 (CATCO) trial, investigators randomly assigned patients to receive remdesivir or standard care, regardless of kidney function. Among 1281 patients (median age 74 years), 34 patients receiving remdesivir and 25 patients receiving standard care had a baseline eGFR less than 30 mL/ min/1.73 m 2. The median eGFR at baseline was 18.9 mL/min/1.73 m2. The patients had a median age of 74 years.

Study: UI Risk Tied to Thigh Muscle Area

GREATER THIGH MUSCLE area is associated with a lower risk for urinary incontinence (UI) among older women, according to study findings presented at the International Continence Society’s 2022 annual meeting in Vienna, Austria.

The study, which included 458 community-dwelling adults aged 60 years or older (227 women and 231)

Urinary incontinence in women more likely in those with greater thigh muscle area.

enrolled in the Baltimore Longitudinal Study of Aging, examined the association between thigh muscle, strength, and specific force and incident UI.

Investigators Scott R. Bauer, MD, of the University of California, San Francisco, and colleagues measured thigh muscle area using mid-femur cross-sectional 10-mm computed tomography images.

Approximately a quarter of each group were on hemodialysis. In the remdesivir group, 61.8% of patients were women and 38.2% were men, whereas in the standard care group, 68% were men and 32% were women.

A post hoc analysis showed that patients receiving remdesivir had nonsignificant 26% decreased odds of allcause mortality, regardless of sex and baseline eGFR, Srinivas Murthy, MD, CM, MHSc, of the University of British Columbia in Vancouver, Canada, and colleagues reported in JAMA Network Open. Among patients with an eGFR less than 30 mL/min/1.73 m 2, the researchers observed no increased risks for transaminitis or toxic kidney effects at day 5 among those who received remdesivir.

In analyses of 248 patients with an eGFR less than 60 mL/min/1.73 m 2 , rates of hospital mortality (35.2% vs 42.1%), new mechanical ventilation (10.6% vs 15.7%), and new dialysis (6.2% vs 5.0%) also did not differ significantly between the remdesivir and standard care groups, respectively, the investigators reported.

No dose adjustments were made for CKD or dialysis. Clinicians administered intravenous remdesivir at a loading dose of 200 mg on day 1, followed by daily 100-mg doses for 9 days or until discharge. The median duration of remdesivir treatment was 10 days.

They defined thigh muscle strength based on maximum concentric 30˚/s knee extensor torque and defined thigh muscle specific force as strength divided by area.

The study population had a mean follow-up duration of 3.2 years. Incident UI developed in 75 women, with 53%, 31%, and 16% experiencing urgency UI, stress UI, and other/mixed UI, respectively, according to the investigators. Incident UI developed in 82 men, with 50%, 19%, and 31% having urgency UI, stress UI, and other/mixed UI, respectively.

Compared with women in the lowest tertile of thigh muscle area, those in the middle and highest tertiles had 49% and 54% lower risk for incident UI, Dr Bauer reported. The investigators observed no association between thigh muscle area and incident UI in men. Thigh muscle strength and specific force were not associated with incident UI in either men or women.

“This novel study providing preliminary evidence for a relationship between thigh muscle area and risk of UI in older women,” the authors concluded in their study abstract. “While we did not observe statistically significant associations between thigh muscle measures and incident UI in older men, our [statistical] power may have been insufficient to detect modest but clinically meaningful effects.” ■

Rates of hospital mortality (40.6% vs 52.0%), new mechanical ventilation (14.8% vs 26.1%), and new dialysis (20.0% vs 21.1%) did not differ significantly between the remdesivir and standard care groups with an eGFR less than 30 mL/min/1.73 m2, respectively, according to the investigators.

“These findings suggest that remdesivir can be safely administered in patients with kidney dysfunction, balancing possible risks and benefits,” Dr Murthy and colleagues wrote. “The need for assessing kidney function in the absence of clinical suspicion before and during outpatient administration of remdesivir can be questioned.”

The Food and Drug Administration approved remdesivir in October 2020 for use in patients older than 12 years hospitalized with COVID-19. ■

BTX-A Found Safe, Effective for OAB in Older Adults

INTRADETRUSOR INJECTION of onabotulinumtoxinA (BTX-A) is safe and effective for the treatment of overactive bladder (OAB) in elderly patients, according to data presented at the International Continence Society’s 2022 annual meeting (ICS 2022) in Vienna, Austria.

Natalia Hernandez, MD, of Houston Methodist Hospital in Texas, and colleagues retrospectively studied 141 patients older than 70 years (124 [88%] women) who received intradetrusor BTX-A injections. Prior to treatment, 132 patients (94%) were voiding spontaneously. Urinary urgency was the most common symptom, occurring in 97.3% of patients, followed by urinary incontinence and daytime frequency in 93% and 85%, respectively.

The most common medications initially prescribed were an anticholinergic (74%) and beta-3 agonists (19%). With respect to doses of BTX-A, 89% and 6% received injections of 100 U and 200 U, respectively.

The researchers found that 73%, 77%, 72.5%, and 68% reported

improvement in incontinence, urinary urgency, daytime urinary frequency, and nighttime frequency, respectively, Dr Hernandez reported.

The investigators also performed a subgroup analysis of 26 patients older than 80 years (22 [85%] female). Initially prescribed medications included anticholinergics (50%) and beta-3 agonists (38%). The most common reason for receiving BTX-A was no response to oral medications. Of the 26 patients, 81% and 73% of patients reported a marked improvement in urinary urgency and urinary incontinence, respectively. The investigators observed symptomatic urinary tract infection in 3 patients (12%).

“BTX-A is well tolerated in patients older than 70 years with significant improvement in all OAB symptom domains and significant reduction of their oral OAB medication needs,” the authors wrote. “This provides an option for patients to limit oral medications with unwanted side effects for this special population potentially at an earlier time in the OAB management algorithm.” ■

The antiviral is not recommended when the eGFR is less than 30 mL/min/1.73 m2.

Ethical Issues in Medicine

BY DAVID J. ALFANDRE, MD, MSPH

During morning clinic, one of your older patients arrives for his appointment with his son. This particular patient had previously attended his appointments alone, but in the past year he has been arriving with a family member. Today, his son tells you that his dad, who lives alone, has been having more trouble remembering to take his medication and pay his bills. He and his siblings have been discussing the patient’s willingness to move into a nearby assisted living facility. The patient asks you how his kids can be helpful when he has trouble making health care decisions for himself.

Facilitating deciding for others is a central part of health care for many clinicians. Although pediatricians and geriatricians are more likely to have to engage family members to help make health care decisions for some of their patients, clinicians in all specialties should understand the principles and procedures for deciding on behalf of others in an ethically strong way.

First and foremost is that adult patients make decisions on their own behalf unless they lack decision-making capacity (DMC) or they voluntarily choose to cede that decision-making authority to another person. DMC is a determination by a health care professional about

to the clinician’s recommendation. However, if the patient is significantly impaired by intoxication and chooses to decline a particular intervention, it may not be unreasonable to question their decision-making ability.

Although critically assessing DMC for the broad range of health care decisions is beyond the scope of this article, clinicians should appreciate some general principles about the process. Patients with DMC should be able to understand the relevant clinical information of the proposed decision, including its risks, benefits, and alternatives; appreciate the consequences of the decision as it relates to them specifically; be able to rationally manipulate the provided information; and clearly communicate a choice.

It is no small matter to decide that a patient lacks DMC, as that can portend significant consequences to the patient’s autonomy. At the same time, allowing patients to make decisions when they lack to capacity can be harmful as well. When patients lack DMC, an authorized individual (often referred to as a surrogate decision maker) must make decisions on their behalf. There is a hierarchy that determines which individual has priority, and this is usually based on state law for clinicians who practice in nonfederal health care settings. Although

close friend) to serve as an authorized decision maker if there is no one else available and they can demonstrate that they know the patient and can represent their best interests. Finally, although a court-appointed guardian could usually be appointed, in practice, this process is often costly and time consuming and impractical for time-sensitive decisions.

When there is no surrogate available on the hierarchy, most states have a legal process by which the health care team can make timely health care decisions on behalf of the patient with varying levels of oversight. These procedural protections help ensure that these vulnerable “unbefriended” patients are not exploited.

reasoning, which essentially translates to what they believe is best for that patient at that time. Finally, even when a patient lacks DMC, the surrogate and the clinician should seek to involve the patient in as much of the decision-making process as possible. This can assist the surrogate to decide as well as to respect the patient’s ability to participate in health care decisions, even if that ability is diminished.

a patient’s ability to make a specific health care decision at a particular point in time. Patients should be presumed to possess DMC unless there is a compelling reason to conclude otherwise. Moreover, DMC determinations should not be based on the content of the decision, but rather on the patient’s decisionmaking process. For example, a patient should not be presumed to lack DMC simply because they have chosen to decline a beneficial treatment contrary

the hierarchy will undoubtedly vary by state (you should consult your local counsel or ethics consultation resources for specifics), the prioritized list of available surrogate decision-makers usually starts with a durable power of attorney for health care (i.e., health care proxy), then legal guardian, spouse, adult child, parent, sibling, or another family member. Some states and jurisdictions allow for someone not on the specific hierarchy of surrogates (e.g., an uncle, niece,

Regardless of who the ultimate surrogate decision makers are, they all have certain ethical responsibilities. These decision makers are not free to make health care decisions however they want or simply to meet their own needs, but rather are obligated to decide based on what the patient would have wanted if it is known. This is referred to as “substituted judgment” and can often be found in the health care documents specified above. When there is insufficient knowledge or documentation of a patient’s preferences for care, surrogates must base their decisions on “best interests”

Strong ethical practices for surrogate decision making help to maximize patients’ bodily autonomy by enhancing their ability to speak for themselves even as illness infringes on their ability to do so. When patients are unable to exercise their rights any longer, they depend on family, friends, and sometimes health care professionals to do the right thing and make those decisions for them based on what the patient would have wanted if known, and if not known, then on their best interest. ■

David J. Alfandre, MD, MSPH, is a health care ethicist and an associate professor in 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 VA National Center for Ethics in Health Care or the US Department of Veterans Affairs.

© LUIS ALVAREZ / GETTY IMAGES

It is no small matter to decide that a patient lacks decision-making capacity, as that can portend significant consequences to the patient’s autonomy.

Surrogate decision makers are obligated to act based on what patients would have wanted, if known

Facilitating deciding for others is a central part of health care for many clinicians.

Practice Management

Peer comparisons might not improve performance but instead decrease job

BY JOHN SCHIESZER

Health care system leaders and policymakers may need to make some structural changes to help prevent mental health problems and job turnover among physicians.

A recent study published in the Proceedings of the National Academy of Sciences suggests that a commonly used behavioral intervention of informing physicians about how their performance compares with that of their peers appears to have backfired. Investigators found it had no statistically significant impact on performance and instead decreased physicians’ job satisfaction and increased burnout.

The team conducted a 5-month field experiment involving 199 primary care physicians and 46,631 patients. The study examined the impact of a peer comparison intervention on physicians’ job performance, job satisfaction, and burnout. The findings suggest that a lack of leadership support may be the key mechanism causing this backfiring effect.

Study investigator Justin Zhang, MD, a resident physician in internal medicine at the University of California, San Francisco, said it is the responsibility of a health system’s leadership to promote physician buy-in to quality improvement efforts. Leadership also needs to provide physician clinics the tools

decreased job satisfaction and increased burnout. The effect on job satisfaction persisted for at least 4 months after the intervention had been discontinued.

The quantitative and qualitative evidence on the mechanisms underlying the unanticipated negative effects in this study highlights the importance of evaluating the psychological costs of behavioral interventions, according to the researchers.

Burnout Pervasive

When policymakers and organizational leaders implement seemingly innocuous behavioral interventions, they need to know how it affects burnout, Dr Zhang said. “Despite many health systems’ transition towards pay-for-performance models, there remain significant opportunities for improvement,” he said.

Burnout among physicians is a pervasive problem that became worse throughout the COVID-19 pandemic. “While our study was conducted specifically within the context of primary care, it is quite possible that these results and implications translate over to medical subspecialties. Health care delivery is becoming increasingly complex,” Dr Zhang said. “As such, it takes a teambased approach with leadership support to be able to deliver excellent patient

empower themselves to navigate those challenges.”

Current trends suggest that organizational leaders need to engage employees in the design phase of an intervention, probe their feelings, and revise the design if needed. David A. Rogers, MD, the UAB (University of Alabama at Birmingham) Medicine Chief Wellness Officer, said the continuing pandemic is exacerbating many previously existing problems. “Physician burnout was already occurring at alarming rates and the magnitude of the problem has grown as we navigate through all of the on-going stresses caused by the pandemic in the social environment of marked polarization,” Dr Rogers said.

assertiveness training, and facilitated discussion groups.

Work Overload

The review’s lead author, Rikinkumar S. Patel, MD, MPH, a child and adolescent psychiatry fellow at Duke University in Durham, North Carolina, said work overload is the main contributor to physician burnout, but it is reversible and preventable. “Burnout has adverse outcomes on physician well-being, patient care, and the health care system,” Dr. Patel said. “Physicians experiencing signs of burnout are more likely to have decreased work productivity, exhaustion, and poor quality of care when compared to their earlier careers.”

they need to implement preventive care measures as seamlessly as possible.

It is common for policymakers and business leaders to use peer comparison information to motivate a range of behaviors. The potential impact of peer comparison interventions on recipients’ well-being is largely unknown, however. The current study revealed that implementation of peer comparison did not significantly improve physicians’ preventive care performance and significantly

care, achieve quality measure goals, while also optimizing physician well-being.”

“Tackling physician burnout requires a top-down approach,” Dr Zhang said. “Health system leaders need to listen to their staff physicians and other medical professionals, understand the areas that they feel like they need more support in, and ultimately implement structural changes to address those identified challenges and/or provide their health care workers the tools to

A growing body of research continues to show that leadership development is essential and much more nuanced and carefully tested interventions are warranted. “Even a seemingly innocent organizational effort like providing performance feedback can be a cause of distress for physicians unless it is accompanied by enlightened leadership,” Dr Rogers said.

According to a review published in 2018 in Behavioral Sciences, systematic application of evidence-based interventions is urgently needed and may include but is not limited to group interventions, mindfulness training,

Physician burnout can increase the economic burden of training and recruiting new staff members when efficient physicians quit because of burnout. “There is a need for management to keep a check on doctors’ physical and behavioral wellbeing,” Dr Patel said. “Self-awareness among physicians can enhance the ability to recognize their vulnerability to burnout, and immediate measures should be taken to overcome and manage fatigue, stress, and accentuate resiliency.” ■

John Schieszer is a freelance medical writer based in Seattle, Washington.

satisfaction and increase burnout

Burnout has adverse outcomes on physician well-being and patient care, a researcher says.

A health system’s leadership is responsible for promoting physician buy-in to quality improvement efforts, an investigator says.