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Despite warranted concerns regarding the overdiagnosis and overtreatment of many cases of biologically indolent prostate cancer, prostate cancer remains the second leading cause of cancer-related death in the United States behind only lung cancer.¹ With current treatment paradigms, nearly all patients who die of prostate cancer first receive androgen-deprivation therapy and then progress to castrate-resistant prostate cancer.

The use of an external urine collection device (EUCD) is an effective way to manage and collect urine leakage in men and women who have urinary incontinence. However, these devices are not indicated for the management of urinary obstruction or urinary retention. The 2009 CDC guidelines noted that an EUCD is an alternative to an indwelling urinary (Foley) catheter in male patients without urinary retention or bladder outlet obstruction.   

Appropriate use:

• Male or female patients who experience urinary incontinence (UI) without urinary retention including long term care residents in nursing homes, patients who are obese and have limited movement, and those patients with UI secondary to neurogenic lower urinary tract dysfunction (NLUTD) without sensory awareness due to paralyzing spinal disorders such as spinal cord injury, transverse myelitis, or progressive multiple sclerosis.
• Patient/caregiver requests for an external device to manage and collect urine leakage.
• For use in a male patient who has undergone prostate surgery (i.e. post-prostatectomy) who is experiencing stress incontinence who needs a containment system to return to work or usual activities (e.g., golfing).
• Daily (not hourly) measurement of urine volume that is required (e.g. hospitalized patient) and cannot be assessed by other volume and urine collection strategies in acute care situations (e.g. acute renal failure work-up, bolus diuretics, fluid management in respiratory failure).
• Single 24-hour or random nonsterile urine sample for diagnostic tests that cannot be obtained by other urine collection strategies.
• To reduce or minimize acute, severe pain that is a result of movement when other urine management strategies are difficult (e.g. turning patient to remove an absorbent pad causes pain).
• Managing overactive bladder symptoms and improving comfort in palliative care patients.
• Use during the night to promote restful sleep and to reduce the risk for falls by minimizing the need to get up to urinate.

Inappropriate use:

• Any type of urinary retention (acute or chronic, with or without bladder outlet obstruction).
• Any use in an uncooperative patient expected to frequently manipulate catheters because of such behavior issues as delirium and dementia.
• Patient or family request in a patient who is continent when there are alternatives for urine containment (e.g. commode, urinal, or bedpan).
• A need for a sterile urine sample for diagnostic tests where specimen obtained from an EUCD is not sterile.

Written by: Diane K. Newman, DNP, ANP-BC, FAAN, Adjunct Professor of Urology in Surgery, Research Investigator Senior, Perelman School of Medicine, Co-Director, Penn Center for Continence and Pelvic Health, Division of Urology, University of Pennsylvania, Philadelphia, Pennsylvania

April 2020

The rapid spread of Coronavirus Disease 2019 (COVID-19), caused by the betacoronavirus SARS-CoV-2, has had dramatic effects throughout the world on healthcare systems with impacts far beyond the patients actually infected with COVID-19.

Patients who manifest severe forms of COVID-19 requiring respiratory support typically require this for prolonged durations, with a mean of 13 days of respiratory support reported by the China Medical Treatment Expert Group for COVID-19.¹ This lengthy requirement for ventilator support and ICU resources, exacerbated by relatively little excess health system capacity to accommodate epidemics, means that healthcare systems can (and have in the case of many hospitals in Italy) become overwhelmed relatively quickly. In an effort to conserve hospital resources, on March 13^th the American College of Surgeons recommended that health systems, hospitals, and surgeons should attempt to minimize, postpone, or outright cancel electively scheduled operations.² This was done with the primary goal to immediately decrease the use of items essential for the care of patients with COVID-19 including ICU beds, ventilators, personal protective equipment, and terminal cleaning supplies. On March 17^th, the American College of Surgeon then provided further guidance on the triage of non-emergent surgeries, including an aggregate assessment of the risk incurred from surgical delays of six to eight weeks or more as compared to the risk (both to the patient and the healthcare system) of proceeding with the operation.³ In the UK, all non-urgent elective surgical procedures have been put on hold for three months to use all of those clinical resources to care for patients with COVID-19.

Most bodies, including the American College of Surgeons, have recommended proceeding with most cancer surgeries. Thus, clinicians and patients must carefully weigh the benefit of proceeding with cancer treatment as scheduled, the risks of COVID-19 to the individual patient, to healthcare workers caring for patients potentially infected with COVID-19, and the need to conserve health care resources. A severe SARS-CoV-2 phenotype is seen more commonly in men and older, more comorbid patients.⁴ Baseline characteristics among 1,591 patients admitted to the ICU in the Lombardy Region, Italy, showed that the median age was 63 years (IQR 56-70), 82% were male, 68% had ≥1 comorbidity, 88% required ventilator support, and the mortality rate was 26%, with a large proportion requiring ongoing ICU level care at the time of data cut-off.⁵ Work from China demonstrated that patients with cancer had a higher incidence of COVID-19 infection than expected in the general population and had a more severe manifestation of the disease with a significantly higher proportion requiring invasive ventilation in the ICU or death.⁶ Patients at increased risk of COVID-19 are comparable to the kidney cancer population, namely more likely male, hypertensive, and with more than one comorbidity.⁵


Thus, considering the differences in the natural history of different cancers may meaningfully change this balance of risks and benefits. Kidney cancer has a wide range of phenotypic presentations ranging from very indolent, incidentally diagnosed small renal masses to large, symptomatic tumors with vascular or adjacent organ invasion and de novo metastatic disease. Previous articles in the UroToday Kidney Cancer Today Center of Excellence have discussed the Epidemiology and Etiology of Kidney Cancer and particular nuances of staging and management for Malignant Renal Tumors. The vast majority of patients have localized disease at the time of presentation. According to Siegel et al., 65% of all patients diagnosed with kidney and renal pelvis tumors between 2007 and 2013 had localized disease at the time of presentation while 16% had regional spread, and 16% had evidence of distant, metastatic disease.⁷

While the effect of delays in surgical intervention has been most thoroughly explored in muscle-invasive bladder cancer and prostate cancer in the urologic literature, both data and inference may help guide the management of patients with kidney cancer at this time. A single previous narrative review has assessed this question,⁸ however, conclusions from this study are limited. In the absence of data, the guidance of care relies on expert opinion, including a collaborative review pre-published in European Urology (Wallis et al.). This article will discuss the impact of potential delays among patients with kidney cancer, providing recommendations as to who can safely defer treatment until after the pandemic is over versus those that should be treated without delay.

While there are no randomized data, numerous institutional studies have demonstrated both the safety and feasibility of active surveillance (AS) with delayed intervention in patients with small renal masses (SRMs).^9,10

Among 457 patients treated at Fox Chase Cancer Center, McIntosh et al. found that rates of delayed intervention were 9%, 22%, 29%, 35%, and 42% at one-, two-, three-, four-, and five-years following diagnosis.¹¹ Importantly, delayed intervention was not associated with overall survival (OS) (hazard ratio [HR] 1.34, 95% confidence interval [CI] 0.79-2.29), and of the 99 patients on AS without delayed intervention for more than five years, only one patient metastasized. Interestingly, they found a median initial linear growth rate was 1.9 mm/year (IQR 0-7) which was not associated with OS.

Data from the University of Michigan has also assessed the effect of delayed resection (at least six months from presentation) after initial surveillance for patients with SRMs.¹² In this study, there were 401 patients that underwent early resection and 94 patients (19%) that underwent delayed resection. The median time to resection was 84 days (IQR 59-121) in the early intervention group and 386 days (IQR 272-702) in the delayed intervention group. Importantly, there was no difference in adverse final pathology (grade 3-4, papillary type 2, sarcomatoid histology, angiomyolipoma with epithelioid features, or stage ≥ pT3) comparing those that underwent early vs late intervention.

Among 497 patients in the DISSRM registry, 223 (43%) chose AS and 274 (57%) chose primary intervention with 21 (9%) eventually undergoing delayed intervention after a period of AS. There was no difference in cancer-specific survival (CSS) at five-years between the groups (primary intervention: 99%; AS 100%, p=0.3) though patients choosing surveillance had lower five-year OS (75% vs 92%), likely attributable to comorbidity which drove their initial selection of surveillance.

Taken together, there is robust data supporting AS for masses < 4cm, even up to five years after the initial diagnosis, without age restriction.^13,14 Thus, delays in the diagnosis and management of these patients during the COVID-19 pandemic is unlikely to meaningfully affect their outcomes.

Although the data is less robust, several studies have assessed the impact of a surgical delay for larger localized kidney tumors (≥pT1b). An institutional cohort from Memorial Sloan Kettering Cancer Center examined 1,278 patients who underwent radical or partial nephrectomy with renal masses > 4 cm between 1995 and 2013. The authors tested the association between surgical wait time and disease upstaging at the time of surgery, as well as two- and five-year recurrence rates.¹⁵ Among these patients, 267 (21%) had a surgical wait time of more than three months, including 82 patients (6%) with a wait time of more than six months. On multivariable analysis, the surgical wait time was not associated with disease upstaging, recurrence or CSS, but longer wait time was associated with worse OS (HR 1.17, 95% CI 1.08-1.27), potentially reflecting comorbidity which necessitated the initial delays.

Similarly, an institutional cohort from the Fox Chase Cancer Center of patients with cT1b/cT2 renal masses assessed the safety of active surveillance.¹⁶ Twenty-three patients (34%) underwent delayed intervention. Over a median follow-up of 32 months (range 6-119), no patients progressed to metastatic disease or died of kidney cancer. The median linear growth rate was 0.34 cm/year (range 0-1.48) suggesting that delays of months to years are unlikely to affect the resectability of these tumors.

Finally, a retrospective review of 722 patients undergoing partial or radical nephrectomy for relatively large kidney tumors (mean tumor size of 6.4 +/- 4.4cm; 64.7% ≥pT1b and 49.0% ≥pT2) from Stec et al. assessed the effect of delays to surgery on survival.¹⁷ They found that the mean time from initial visit to surgery was 1.2 months (range 0-30 months) and that 64.1% of patients underwent surgery within 30 days of initial visit and 94.3% within three months. The authors found no difference in OS for patients receiving early vs. late surgery, whether using a threshold of one month (p=0.87), two months (p=0.46), three months (p=0.71), or six months (p=0.75). However, T-stage was a significant predictor of recurrence-free survival (RFS), independent of time to surgery.

There are essentially no available data on the effect of delays in treating patients with locally advanced kidney cancer. However, several large institutional studies have described timing of preoperative imaging for assessing renal vein/inferior vena cava (IVC) thrombus, which may guide the urgency of surgical timing. While Woodruff et al. recommended the longest interval between imaging (CT/MRI) and surgery being no longer than 30 days,¹⁸ studies from the Mayo Clinic and Berlin, Germany report a median interval from imaging to resection of 4 and 16 days, respectively.^19,20 As a result, the collaborative review pre-published in European Urology suggested that these patients should be prioritized for intervention given the locally advanced nature of their disease, unknown risk of delayed resection, and potential for significant symptomatic complications including bleeding and IVC occlusion.

In contrast, in patients with known metastatic kidney cancer, cytoreductive nephrectomy during the ongoing pandemic was not recommended in this collaborative review on account of the evidence from the CARMENA trial which failed to demonstrate a survival benefit to the addition of cytoreductive to systemic therapy with sunitinib.²¹ Additionally, the SURTIME trial found that upfront systemic therapy followed by cytoreductive nephrectomy was associated with longer survival than patients who received upfront cytoreduction followed by systemic therapy.²²

The question of when to initiate systemic therapy in patients with metastatic kidney cancer is also pertinent during this pandemic and depends on symptoms, patient comorbidities, and tumor risk stratification. In treatment-naïve patients with favorable and intermediate-risk disease who are asymptomatic or minimally symptomatic with limited disease burden, a number of studies, including two narrative reviews^23,24 and two prospective trials,^25,26 have assessed the safety and feasibility of delaying the initiation of systemic therapy. In the largest prospective study of surveillance in patients with metastatic kidney cancer, Rini et al. enrolled fifty-two asymptomatic patients in a Phase II trial.²⁶ All but one patient had favorable (23%) or intermediate (75%) risk disease according to IMDC criteria with the vast majority (80%) of patients having only one or two organ sites with metastases. The median time on surveillance was 14.9 months and 37 of 43 patients experiencing RECIST-defined disease progression started systemic treatment. The median PFS and OS from the start of surveillance was 9.4 and 44.5 months, respectively. In a smaller study of 15 patients who received CN followed by observation until progression, Wong et al. found a median time to progression of eight weeks and a median OS of 25 months.²⁵ Neither of these studies have compared outcomes with patients who started systemic therapy upfront. However, this has been assessed in two large retrospective studies. Among a European cohort of patients ineligible for active surveillance, Iacovelli and colleagues found that a delay of more than six weeks in the initiation of systemic therapy did not significantly affect the cancer-specific outcomes.²⁷ Further, delayed treatment initiation was not independently associated with worse OS in an analysis based on the National Cancer Database utilizing multivariable logistic regression analyses.²⁸

There is no evidence to guide the choice of systemic therapy during the COVID-19 pandemic and thus, standard guideline recommendations should prevail. However, at least theoretically, the risk of severe adverse reactions associated with immunotherapy using checkpoint inhibitors, as well as the requirement for infusion, may preferentially support the use of VEGF-targeted therapy with the convenience of oral administration.

Written by: Zachary Klaassen, MD, MSc, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, Atlanta, Georgia

Published Date: April 2020

Before the POUT Trial

Implications and Future Considerations Following the POUT Trial

Currently, there is a global pandemic surrounding the spread of betacoronavirus SARS-CoV-2 leading to Coronavirus Disease 2019 (COVID-19). The rapid spread to all corners of the globe has had tremendous health and economic implications, including the appropriate allocation of healthcare resources. Considering that hospitals may be overwhelmed quickly given the need for a proportion of patients that require hospitalization with possible ventilator support, there is a necessity to decrease the use of items essential for the care of patients with COVID-19 including ICU beds, ventilators, personal protective equipment, and terminal cleaning supplies. This includes reassessing the priority and implications of treatments, including prostate cancer screening. 

Adherence to infection control principles, standard supplies, procedures and processes

• Hand hygiene - the most important factor in preventing nosocomial infections
• Aseptic catheter insertion procedure
• Proper Foley catheter maintenance, education, and care by nursing staff
• Foley catheter use surveillance and feedback

The rapid spread of Coronavirus Disease 2019 (COVID-19), caused by the betacoronavirus SARS-CoV-2, throughout the world has had dramatic effects on healthcare systems with impacts far beyond the patients actually infected with COVID-19.

Patients who manifest severe forms of COVID-19 requiring respiratory support typically require this for prolonged durations, with a mean of 13 days of respiratory support reported by the China Medical Treatment Expert Group for COVID-19.¹ This lengthy requirement for ventilator support and ICU resources, exacerbated by relatively little excess health system capacity to accommodate epidemics, means that healthcare systems can (and have in the case of many hospitals in Italy) become overwhelmed relatively quickly. In an effort to conserve hospital resources, the American College of Surgeons on March 13^th recommended that health systems, hospitals, and surgeons should attempt to minimize, postpone, or outright cancel electively scheduled operations.² This was done with the primary goal to immediately decrease the use of items essential for the care of patients with COVID-19 including ICU beds, ventilators, personal protective equipment, and terminal cleaning supplies. On March 17^th, the American College of Surgeon then provided further guidance on the triage of non-emergent surgeries, including an aggregate assessment of the risk incurred from surgical delays of six to eight weeks or more as compared to the risk (both to the patient and the healthcare system) of proceeding with the operation.³ In the UK, all non-urgent elective surgical procedures have been put on hold for three months to use all of those clinical resources to care for patients with COVID-19.

Most bodies, including the American College of Surgeons, have recommended proceeding with most cancer surgeries. Thus, clinicians and patients must carefully weigh the benefit of proceeding with cancer treatment as scheduled, the risks of COVID-19 to the individual patient, to health care workers caring for patients potentially infected with COVID-19, and the need to conserve health care resources. A severe SARS-CoV-2 phenotype is seen more commonly in men and older, more comorbid patients.⁴ These characteristics are common in many patients with urologic malignancies, particularly those with bladder cancer. Baseline characteristics among 1,591 patients admitted to the ICU in the Lombardy Region, Italy showed that the median age was 63 years (IQR 56-70), 82% were male, 68% had ≥1 comorbidity, 88% required ventilator support, and the mortality rate was 26%, with a large proportion requiring ongoing ICU level care at the time of data cut-off.⁵ Work from China demonstrated that patients with cancer had a higher incidence of COVID-19 infection than expected in the general population and had a more severe manifestation of the disease with a significantly higher proportion requiring invasive ventilation in the ICU or death.⁶ Thus, considering differences in the natural history of different cancers may meaningfully change this balance of risks and benefits.

In the urologic literature, the effect of delays in surgical intervention has been most thoroughly explored in muscle-invasive bladder cancer and prostate cancer. In bladder cancer, these studies have predominately assessed the association between time from transurethral resection of bladder tumor (TURBT) to radical cystectomy. At least nineteen studies have been published assessing this research question. Published October 23, 2019, in European Urology Oncology, Dr. Russell and colleagues provide a contemporary systematic review and meta-analysis of these data.⁷ The authors undertook a systematic review of Medline®, Embase®, and Ovid® for randomized trials and observational studies assessing the association between delay in treatment and survival (overall or bladder cancer-specific) for patients with bladder cancer. Among 399 identified articles, the authors included 19 studies in systematic review and 10 in meta-analysis. Utilizing the Risk of Bias in Non-randomised studies – of Interventions (ROBINS-I) and the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) criteria, the authors assessed that most studies were of good quality with low or moderate risk of bias. To account for this, the authors performed “leave out one” sensitivity analyses.

Perhaps the most striking conclusion of this systematic review is the considerable heterogeneity in the source literature, including in methodology. There was considerable variation in the nature of the delay investigated: from the diagnosis of bladder cancer to radical cystectomy (10 studies), from TURBT to radical cystectomy (seven studies), from first clinic visit to radical cystectomy (or radiotherapy; one study), from referral to first treatment (one study), and from neoadjuvant chemotherapy to radical cystectomy (four studies). Additionally, the delay interval was operationalized inconsistently across studies with some using time as a continuous variable, some utilizing splines to model a non-linear relationship, and many utilizing a categorical approach with a variety of thresholds.

Among these studies, a number assessed reasons for delay. Identified reasons for delay included scheduling, seeking multiple medical opinions, social issues, misdiagnosis, and patient comorbidity.

Assessing the delay between bladder cancer and survival, four of nine studies found a significant association between delay from diagnosis to radical cystectomy and survival, with a number concluding that tumor stage was a potential confounder in this relationship. Russell and colleagues meta-analyzed three studies with suitable data and found an increased risk of death for patients with significant delays between diagnosis and radical cystectomy (hazard ratio [HR] 1.34, 95% confidence interval [CI] 1.18-1.53; I²=0%).⁷

Operationalizing delay as the interval between TURBT and radical cystectomy, four of six studies found an association between this time and survival; a meta-analysis of five studies with suitable data for pooling found a borderline non-significant increased risk of overall mortality (odds ratio 1.18, 95% confident interval 0.99-1.41), with significant between study heterogeneity (I²=73%).⁷ Utilizing a cubic spline to model the non-linear relationship, Kulkarni and colleagues found that the risk of death began to rise beginning at 40 days between TURBT and radical cystectomy.⁸

An additional five studies assess the association between the time duration between the completion of neoadjuvant chemotherapy and radical cystectomy and survival. Two demonstrated that prolonged durations between neoadjuvant chemotherapy and radical cystectomy was associated with adverse survival outcomes and an additional one demonstrated upstaging was associated with delays. Boeri et al. found that patients who had greater than 10 weeks between the last cycle of neoadjuvant chemotherapy and radical cystectomy had significantly lower cancer-specific and overall survival.⁹ Chu et al. found similar results¹⁰ while three other analyses failed to support these results. A meta-analysis of three studies with data suitable for pooling failed to demonstrate a significant association between delays from the end of neoadjuvant chemotherapy to radical cystectomy with survival (HR 1.04, 95% CI 0.93-1.16; I²=82%).⁷

Particularly relevant in the context of the COVID-19 pandemic, Audenet and colleagues found that delays to neoadjuvant chemotherapy of greater than eight weeks were associated with an increased risk of upstaging, while they found no harm in delays up to six months from diagnosis to radical cystectomy, assuming that neoadjuvant chemotherapy was administered in the meantime.¹¹

While the meta-analysis of Russell and colleagues focused on patients with urothelial histology, recently Lin-Brande examined outcomes for patients with variant histology undergoing radical cystectomy.¹² In this analysis, patients with variant histology had a similar time from diagnosis to radical cystectomy as those with urothelial histology. In this cohort, delays from diagnosis to radical cystectomy were associated with worse overall survival (HR 1.36, 95% CI 1.11-1.65 per month of delay) after adjusting for relevant clinicopathologic features. The authors then subsequently dichotomized surgical delays using thresholds of four-, eight-, and 12-weeks. On multivariable analysis, no difference in overall survival was apparent when “early” versus “late” was dichotomized at four weeks (hazard ratio 0.92, 95% CI 0.32-2.59) or eight weeks (HR 1.50, 95% CI 0.68-3.29) but significant differences were apparent when delayed surgery was defined as that beyond 12 weeks following diagnosis (HR 3.45, 95% CI 1.51-7.86).

There is somewhat less evidence in patients with non-muscle invasive disease, with significant differences between patients with low-grade and high-grade disease. Low-grade non-muscle invasive bladder cancer has low cancer-specific mortality¹³ and there is no evidence of harm from delays in management.^14-16

In contrast, for patients with high-grade non-muscle invasive disease, progression to muscle invasion/metastases occurs in 15-40% and 10-20% of patients may die from bladder cancer.^17,18 In patients who underwent radical cystectomy for recurrent non-muscle invasive bladder cancer following Bacillus Calmette-Guerin (BCG) with or without further intravesical therapy, the delay caused by an additional (unsuccessful) course of intravesical therapy did not result in differences in five-year overall or cancer-specific survival despite a median delay of 1.7 years.¹⁹ In contrast, among patients with non-muscle invasive (cT1) micropapillary bladder cancer treated with upfront radical cystectomy or intravesical BCG, Willis et al. demonstrated significantly poorer survival outcomes for patients who underwent initial intravesical therapy.²⁰

In the absence of data, guidance on the care of patients with high-grade non-muscle invasive bladder cancer has relied upon expert guidance. A collaborative review pre-published in European Urology suggested that these patients should receive induction BCG and at least one course of maintenance therapy as the first-line treatment. The authors recommended that re-resection should be continued for patients with pT1 disease while this may be omitted for those with pTa and muscle in the initial resection.

The data regarding delays to radical cystectomy demonstrate considerable heterogeneity with mixed results. This is in large part due to varying definitions of a delay, despite the threshold of 12 weeks advocated in EAU guidelines.²¹ However, in aggregate, these data suggest that prolonged delays (likely 90 days although potentially as short as 40 days) between bladder cancer diagnosis or TURBT and radical cystectomy are associated with worse survival. However, the data are mixed and pooled results demonstrate considerable heterogeneity. Further, when neoadjuvant chemotherapy is employed, delays to radical cystectomy no longer appear to be significant. Finally, an analysis of funnel plots indicates that there is a publication bias towards studies which demonstrate worse survival associated with delays suggesting that this finding may be exaggerated in the literature.⁷

A recent multi-institutional analysis from Campi and colleagues assessed the proportion of patients undergoing urologic oncology surgery who had “nondeferrable” indications for treatment.²² The authors identified 2387 patients undergoing radical cystectomy, radical nephroureterectomy, nephrectomy, and radical prostatectomy in the past 12 months at San Luigi Hospital in Turin, San Raffaele Hospital in Milan, and Careggi Hospital in Florence. Assessing patients undergoing radical cystectomy, the authors considered all cases “nondeferrable”. Radical cystectomy comprised 36.2% of all so-called high-priority or nondeferrable cases. They also noted that a large proportion of these patients (50%) are at elevated perioperative risk (defined at American Society of Anesthesiologists score ≥ 3).

In the context of non-muscle invasive disease, delays appear to be significantly more likely to cause harm in patients with high-grade than low-grade disease. However, the evidence base in non-muscle invasive disease is much weaker than for muscle-invasive bladder cancer.

However, when considering delays in performing TURBT, it is not always apparent whether the patient has non-muscle invasive or muscle-invasive disease. Wallace and colleagues examined delays throughout the trajectory of patients with a new diagnosis of urothelial carcinoma, including a preponderance of non-muscle invasive disease (pTa = 51% and pT1 = 22%).²³ The authors divided delays in the evaluation of these patients into three: from initial symptom onset to general practitioner presentation (patient-derived delay), from general practitioner presentation to hospital referral (general practitioner-derived delay), and from hospital referral to TURBT (hospital-derived delay). Shorter delays from initial symptom onset to general practitioner presentation were associated with lower tumor stage and improved five-year survival. In this analysis, the authors dichotomized this patient-derived delay at 14 days. Notably, patients with shorter general practitioner-derived delay had worse survival, likely reflecting a selection bias in which patients with particularly worrisome presentations received expedited care. Finally, hospital-derived delays were not significantly associated with survival, whether adjusted for tumor stage or not. When considered in aggregate, total delays from initial symptom onset to TURBT were not significantly associated with survival.

During the COVID-19 pandemic, there will be regional variations in the risk of infection and availability of resources, both with regards to medical treatment and operating room availability. Expert recommendations from the pre-published paper in European Urology suggest it is reasonable that patients with high-grade NMIBC should undergo induction BCG and maintenance therapy if possible. For high-risk NMIBC, radical cystectomy should still be offered if the resources are feasible and the patient’s comorbidity profile does not place them at higher post-operative COVID-19 risk. Based on the available literature, delays in radical cystectomy of up to three months may be safe for muscle-invasive bladder cancer. However, clinicians should prioritize high-grade bladder cancer (NMIBC and muscle-invasive) over other urologic oncology procedures during COVID-19 restrictions.

Written by: Zachary Klaassen, MD, MSc, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, Atlanta, Georgia

Published Date: April 20th, 2020

First Published April 2, 2020

The ongoing pandemic involving severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and its resulting coronavirus disease 2019 (COVID-19) has caused widespread infection worldwide, with over 660,000 confirmed cases as of March 28, 2020 and nearly 31,000 deaths.¹ Data from the Italian National Institute of Health (Istituto Superiore di Sanità [ISS]) where fatalities are thus far the highest suggest a fatality rate of 7.2%, significantly higher than that which has been observed in other countries.² Elderly patients are at greatest risk of mortality from COVID-19, and approximately 23% of the Italian populace is aged 65 years or older, making the country particularly vulnerable.²

A newly published systematic review and meta-analysis: Evidence-based Assessment of Current and Emerging Bladder-sparing Therapies for Non–muscle-invasive Bladder Cancer After Bacillus Calmette-Guerin Therapy: A Systematic Review and Meta-analysis 

The shape and material of external urine collection devices (EUCD) have changed over the past 20 years. Historically, most EUCDs were made from latex that allowed for flexibility but also increased the risk of an allergic reaction. Latex-based sheath devices are still available but more recent ones are constructed from non-allergenic silicone. Most EUCDs are open at the distal end (tip) allowing urine to drain through attached tubing connected to a drainage bag. 

There are two broad categories, those that are single-use disposable products (in-place for only one to two days), and those that are reusable for multiple times.

If the EUCD has adhesive, prior to its application, the skin should be cleansed and pubic hair at the base of the penis in men and the perineum in women should be removed. The hair should be trimmed, not shaved, because shaving causes more irritation. The EUCD can be removed by loosening the adhesive with a warm, wet cloth. 

We are categorizing the types of EUCDs as follows:



Written by: Diane K. Newman, DNP, ANP-BC, FAAN, Adjunct Professor of Urology in Surgery, Research Investigator Senior, Perelman School of Medicine, Co-Director, Penn Center for Continence and Pelvic Health, Division of Urology, University of Pennsylvania, Philadelphia, Pennsylvania

April 2020

An external urine collection device (EUCD) may be external and less invasive but they are not free of risks. Complications and adverse effects include skin lesion/ulceration and breakdown from pressure necrosis and moisture, urethral fistula or very rarely, gangrene of the penis. The majority of complications involve perineal/genital skin issues, primarily occurring in 15-30% of male patients and involve external penile shaft problems.

Early years: cytokine therapy

A new standard: molecularly targeted agents

What’s old is new: immunotherapy for RCC

The next frontier: combinations of targeted therapy and immunotherapy

Dead-ends

Integration of treatment options for patients with metastatic ccRCC

What about surgery?

Upper tract urothelial carcinoma, which may affect the renal pelvis or ureter, is a relatively rare disease, accounting for less than 10% of all urothelial carcinomas.¹ The etiology of this uncommon cancer is discussed in more detail in a previous UroToday Center of Excellence article.

Patients with advanced prostate cancer are at significant risk of skeletal-related events (SREs) due to a complex interplay between bone health and prostate cancer due to cancer biology and the predilection of prostate cancer to spread to bone, the toxicity of prostate cancer treatments, and shared epidemiology of the two conditions.

Skeletal-related events are used to denote events related to osseous metastases, including pathologic bone fractures, spinal cord compression, orthopedic surgical intervention, and palliative radiation directed at the bone.¹ This definition has been widely used in the design of randomized controlled trials and for drug approval. In some circumstances, authors include a change in systemic anti-neoplastic therapy as a result of bony pain in the definition of skeletal-related events. The key to this definition is that skeletal-related events may be clinically manifested due to symptoms or only radiographically detected. Thus, skeletal-related events may or may not be symptomatic. In contrast, symptomatic skeletal-related events (SSEs) is a relatively newer outcome representing a subset of skeletal-related events which symptomatically affect the patient experience. This outcome was first used in the Alpharadin in Symptomatic Prostate Cancer (ALSYMPCA) trial,² wherein symptomatic skeletal-related events were defined as bone-directed radiotherapy to relieve bony pain, new symptomatic pathologic fractures, spinal cord compression, or tumor-related orthopedic surgery. While there is a significant overlap between these conditions, there are important differences that relate to both study design and patient care: namely, detection of SREs requires routine radiographic evaluation to detect asymptomatic skeletal-related events while detection of SSEs can be driven by patient evaluation.

Skeletal related events contribute significantly to the disease-related morbidity and mortality of prostate cancer, in addition to being very costly. A range of lifestyle, nutritional, and pharmaceutical interventions can be undertaken to decrease the risk of skeletal-related events in patients with advanced prostate cancer.

Lifestyle and nutrition-based interventions

These recommendations are not unique to patients with prostate cancer, but rather apply to all men with osteoporosis or decreased bone mineral density to reduce the risk of fractures.

The Endocrine Society Clinical Practice Guideline on Osteoporosis in Men recommends the following lifestyle interventions:³

1. Calcium intake: it is recommended that men with or at risk for osteoporosis consume 1000 to 1200 mg of calcium daily. While dietary sources are preferable, calcium supplementation should be used if dietary calcium intake is inadequate.
2. Vitamin D intake: men with low vitamin D levels (< 30 ng/mL or < 75 nmol/L) should receive vitamin D supplementation to raise serum vitamin D levels to at least these levels.
3. Exercise: men at risk of osteoporosis are recommended to participate in weight-bearing activities at least three or four times per week, for 30 to 40 minutes per session.
4. Alcohol intake: it is recommended that men at risk of osteoporosis reduce their alcohol intake to fewer than three units of alcohol. One unit of alcohol is defined as 10 mL of pure alcohol. This amount could be found in 25 mL of spirits (40% alcohol by volume), one third to one half a pint of beer (5-6% alcohol by volume), or half a standard glass of wine (12% alcohol by volume).
5. Smoking cessation: it is recommended that all men at risk of osteoporosis stop smoking.

The American Urological Association 2018 Amendment of the Castration-Resistant Prostate Cancer similarly endorses preventative therapy in the form of supplemental calcium and vitamin D in men with castration-resistant prostate cancer.⁴ However, such interventions are likely advisable much earlier in the disease trajectory given the relatively minor risks of these supplements in contrast to the potentially debilitating and costly consequences of skeletal-related events. To this end, the NCCN and the National Osteoporosis Foundation recommend these interventions in all men over the age of 50 years who are receiving androgen deprivation therapy.

Pharmacologic interventions

In addition to calcium and vitamin D as highlighted above, the American Urological Association 2018 Amendment of the Castration-Resistant Prostate Cancer endorses pharmacotherapy with denosumab or zoledronic acid in men with castration-resistant prostate cancer.⁴

While further indications exist, the Endocrine Society Clinical Practice Guideline on Osteoporosis in Men recommends pharmacologic therapy in men at high risk for fracture based on, but not limited to, the following factors:³

1. Men with a history of previous non-traumatic hip or vertebral fracture.
2. Men with bone mineral density (T-score) that is 2.5 standard deviations or more below the mean of normal young white men, in the absence of spine or hip fractures.
3. Men with a bone mineral density (T-score) from 1.0 to 2.5 standard deviations who also have an increased risk of fracture. In the United States, the suggested criteria for increased risk of fracture are a 10-year risk of any fracture equal to or exceeding 20% or a 10-year risk of hip fracture equal to or exceeding 3%, as determined using the FRAX tool. In other regions, the Guidelines recommend the utilization of region-specific guidelines.
4. Men who are receiving long-term glucocorticoid treatment in significant doses defined by the 2010 American Society of Rheumatology as > 7.5 ng per day of prednisone or equivalent.

Pharmaceuticals - bisphosphonates

Bisphosphonates were among the first agents successfully used to prevent skeletal-related events in advanced prostate cancer. They function by reducing bone resorption through a variety of mechanisms including decreased osteoclast differentiation and survival and increased osteoblast survival. To do so, they compete with pyrophosphate for hydroxyapatite crystal binding sites, thus reducing osteoclast adherence to the bone. While there are a number of bisphosphonates used for a variety of clinical indications, zoledronic acid is most commonly used in patients with metastatic prostate cancer due to the Zometa 039 trial which demonstrated a reduction in SREs for patients who received zoledronic acid as compared to placebo.⁵ Based on these data, zoledronic acid is the only bisphosphonate approved for the prevention of skeletal-related events in men with metastatic prostate cancer.

Pharmaceuticals - denosumab

Denosumab is another agent which targets osteoclast activity. Bone exists in homeostasis between formation (driven by osteoblasts) and resorption (driven by osteoclasts). This homeostasis is regulated by the RANK (receptor activator of nuclear factor κB)/RANK-ligand system. Denosumab is a fully human monoclonal antibody that targets the RANK-ligand by mimicking OPG. Denosumab was first examined in postmenopausal women to prevent the development of osteoporosis and reduce the risk of fracture. Subsequently, denosumab was examined in women with breast cancer. Most relevantly, the Denosumab Protocol 20050103 compared denosumab and zoledronic acid in 1901 men with castrate-resistant prostate cancer.⁶ After a median follow-up of approximately one year, patients receiving denosumab had a significantly prolonged time to first-SRE (3.6 months incremental benefit, hazard ratio 0.82, 95% confidence interval 0.71 to 0.95). As a result of these data, denosumab was approved for the prevention of SREs in patients with metastatic solid tumors.

Pharmaceuticals – radio-isotopes

In addition to these osteoclast targeting agents, radio-isotopes may be used in the prevention of skeletal-related events. While beta-emitting particles (strontium-89 and samarium-153) may be used in the palliation of disease-related bony pain, they don’t have proven benefit in the prevention of SREs. In contrast, the alpha-emitting particle radium-223 has proven both palliative benefit as well as improvements in time to first SRE and overall survival. In the pivotal ALSYMPCA trial, 922 men with castrate-resistant prostate cancer and at least two symptomatic bony metastases who had either previously received or were unfit to receive docetaxel were randomized to radium-223 or placebo. Patients receiving radium-223 had significant improvements in time to first SRE (incremental benefit 5.2 months) as well as overall survival (incremental benefit in median survival of 2.8 months).²

Approach to preventing skeletal-related events

Philosophically, there are a number of times in the natural history of prostate cancer where a clinician may intervene to reduce the risk of prostate cancer related skeletal-related events. These relate to the complex interplay between prostate cancer and bone disease.

First, treatment may be directed at reducing or preventing fragility fractures due to prostate cancer-related therapy. In this disease space, lifestyle and nutrition-based interventions are paramount and are recommended by AUA guidelines as well as the National Comprehensive Cancer Network (NCCN). Pharmacologic interventions, including the use of osteoclast targeting therapies (bisphosphonates and RANK-ligand inhibitors), should be considered in this setting for patients at increased risk of fragility related fracture. Denosumab is FDA approved for this indication on the basis of the HALT 138 trial which found an increase in bone mineral density and a decrease in vertebral fractures among men receiving ADT for non-metastatic hormone-sensitive prostate cancer who receiving denosumab versus placebo.

Second, treatment may be directed at preventing bone metastases. In this disease space, bone-targeting agents including bisphosphonates and denosumab have been examined. The MRC PR04 trial demonstrated no benefit to clodronate in metastasis-free survival. Unfortunately, the Zometa 704 trial assessing the role of zoledronic acid in men with non-metastatic castration-resistant prostate cancer failed to accrue. However, the ZEUS trial accrued 1393 men with high-risk localized prostate cancer. Treatment with zoledronic acid failed to demonstrate an improvement in bone metastasis compared to placebo.⁷ The Denosumab Protocol 20050147 randomized men with high-risk nonmetastatic castrate-resistant prostate cancer to denosumab or placebo. Men receiving denosumab had prolonged metastasis-free survival (incremental benefit of 4.2 months).⁸

However, other approaches utilizing the suppression of the androgen axis in patients with non-metastatic castration-resistant prostate cancer (enzalutamide, apalutamide, and darolutamide) have demonstrated improvements in metastasis-free survival. While not a primary endpoint of these studies, it would be anticipated that delaying metastasis may improve skeletal-related events in these patients.

Third, we may seek to prevent skeletal-related events in men with known metastatic prostate cancer. This applies whether these men are in the castrate-sensitive or castrate-resistant disease space and it is here that the bulk of the evidence for prevention of SREs lies. In men with castrate-sensitive disease, CALGB 90202 demonstrated no improvement in skeletal-related events with the administration of zoledronic acid while castrate-sensitive rather than delayed initiation at the time of castration resistance.⁹ In contrast, there is significant evidence for the role of bone targeting agents in men with castrate-resistant disease. As previously mentioned, Zometa 039 demonstrated improvements in SREs for men receiving zoledronic acid compared with a placebo. Interestingly, CGP 032 and INT 05 failed to demonstrate a benefit to pamidronate. Thus, zoledronic acid is the only bisphosphonate approved in this space. The Denosumab Protocol 20050103 demonstrated an improvement in time to first SRE, as previously mentioned. Further, radio-isotope therapy using radium-223 was demonstrated in ALSYMPCA to improve time to first SRE in men with castrate-resistant prostate cancer and at least two symptomatic bony metastases.

Written by:  Zachary Klaassen, MD, MSc, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, Twitter: @zklaassen_md

Published Date: February 2020