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Germline testing indications for prostate cancer (PCa) have rapidly expanded and have been catapulted by precision medicine and precision management.^1,2 In particular, testing for mutations in DNA repair genes such as in BRCA2, BRCA1, ATM, and other DNA repair genes, has taken front-stage due to the clinical activity of poly (ADP-ribose) polymerase (PARP) inhibitors in metastatic, castration-resistant prostate cancer (mCRPC).^3-7 Phase II trial data supported the U.S. Federal Drug Administration (FDA) designations for olaparib, rucaparib, and niraparib due to demonstrated response rates particularly among men with BRCA2 mutations along with other DNA repair genes.^5-7 Excitingly, the FDA has recently approved two PARP inhibitors for mCRPC. Rucaparib was granted accelerated approval for BRCA1/2-mutated mCRPC with prior treatment with androgen receptor-directed therapy and taxane-based chemotherapy based on TRITON2.⁵ Olaparib was FDA-approved for the treatment of mCRPC in men with deleterious or suspected deleterious germline or somatic homologous recombination repair gene mutations who have progressed following prior treatment with enzalutamide or abiraterone based on PROfound.⁴ These approvals provide exciting therapeutic options for men with mCRPC and will increase the role of germline testing for DNA repair mutations. Furthermore, the National Comprehensive Cancer Network (NCCN) guidelines recommend germline testing for DNA repair mutations in all men with mCRPC, with additional testing criteria proposed.^8,9 The international Philadelphia Prostate Cancer Consensus Conference 2019 has provided significant multidisciplinary guidance regarding germline testing for DNA repair mutations across the stage spectrum, along with strategies for implementation of genetic counseling and germline testing.¹ Therefore, understanding the role of germline testing in PCa is now critical to urologic and oncology practice for this disease. Here, we will address who should be considered for germline testing, when germline testing may influence treatment and management, and how to implement germline testing involving provider practices and genetic counseling.

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

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. 

What are the most common genomic aberrations seen in DNA damage response (DDR) pathways in advanced prostate cancer?

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

Prostate cancer is a clinically heterogeneous disease with many patients having an indolent course requiring no interventions and others who either present with or progress to metastasis. While underlying dominant driving mutations are not widespread, there have been a number of key genomic mutations that have been consistently identified in prostate cancer patients, across the disease spectrum including gene fusion/chromosomal

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

Executive Summary

Imaging is often used to evaluate men with biochemical recurrence (BCR) of prostate cancer after definitive primary treatment (radical prostatectomy [RP] or radiotherapy [RT]). The goal of imaging is to identify the source of elevated or rising serum prostate-specific antigen (PSA) levels because subsequent management depends on disease location and extent.

Background

Upper tract urothelial carcinoma (UTUC), 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.

While radical nephroureterectomy remains the gold standard treatment for patients with upper tract urothelial carcinoma, this approach may not be suitable for some patients and for some tumors. Certainly, for patients with a relatively low volume of low-grade tumors, complete surgical extirpation of a renal unit is likely over treatment.

A recent UroToday Center of Excellence article examined the indications for nephron-sparing approaches, as well as a number of approaches themselves. To briefly summarize, nephron-sparing approaches may be indicated for both imperative and elective reasons. While radical nephroureterectomy should still be considered on the basis of tumor characteristics in patients for whom this will render them dialysis-dependent, most imperative indications center on the risk of renal insufficiency: (i) a solitary functioning kidney, (ii) bilateral upper tract urothelial cancer, (iii) baseline renal insufficiency, (iv) poor candidacy for hemodialysis or renal transplantation, and (v) significant comorbidities. In addition to these imperative indications, elective nephron-sparing approaches may be considered for patients with low-risk/low-grade non-muscle invasive disease. Notably, as highlighted by the 2017 European Association of Urology Guidelines on upper tract urothelial cancer,² ureteroscopic ablation of these tumors should not be utilized for patients with a high volume of tumor, even when it is low-grade, if complete resection is not feasible.

In patients for whom nephron-sparing approaches are being considered, a variety of techniques exist,^3-5 including ureteroscopic and percutaneous surgical approaches. Ureteroscopically, some tumors are relatively or completely inaccessible, particularly those in the lower calyceal system.  

As with urothelial carcinoma of the bladder, patients with non-invasive upper tract urothelial carcinoma have a high risk of recurrence when managed endoscopically. This is exacerbated, compared to non-muscle invasive bladder cancer (NMIBC), with the limitations of endoscopic resection in upper tract disease. In patients managed with ureteroscopic resection, in a systematic review of small (<100 patients) retrospective studies, Petros et al. found a pooled upper tract recurrence rate of 65% at 24-58 months median follow-up.³ In addition, bladder recurrence rates were high (44%). However, progression to radical resection occurred in only 0-33%. Rates of cancer-specific survival were high (70-100%) though overall survival was not as good (35-100%), reflecting the comorbidity profile of patients selected for this approach. Similar results were observed for patients managed with percutaneous surgery: comparably high local recurrence rates (40%) though somewhat lower bladder recurrence rates (24%).³

In patients with NMIBC, topical therapy (with Bacillus Calmette–Guérin (BCG) or chemotherapy) is well established in patients with non-muscle invasive bladder cancer as treatment with BCG has been shown to decrease rates of recurrence.⁶ As a result, this approach is both guideline-supported and widely adopted. In contrast, topical approaches have been much less widely used in patients with non-invasive UTUC. Dr. Nepple and colleagues undertook a review of topical treatment of UTUC, highlighting that upper tract treatment with intra-luminal agents can be problematic due to technical considerations of allowing surface contact.⁷ They describe an approach utilizing office-based flexible cystoscopy for ureteral catheterization followed by instillation of low-dose BCG with interferon. This approach was repeated weekly for six sessions. In their review of the literature, they identified eight studies reporting on the use of adjuvant topical therapy following endoscopic treatment with variable success rates.

In addition to instillation via a ureteral catheter, others have described instillation using percutaneous nephrostomy tubes and bladder instillations in the setting of indwelling ureteral stents with reliance on passive reflux.^7,8 However, this is associated with a significant patient and healthcare system burdens and questionable efficacy. One of the primary challenges is difficulty concentrating therapeutic levels of these agents in the upper tract for more than a brief period of time as a result of rapid emptying of the renal pelvis and ureter.

Among agents used in urothelial carcinoma of the bladder, mitomycin C exposure time to the urothelium is critical for its efficacy.⁹ In order to improve the dwell time of mitomycin C in the upper tract, MitoGel™ was developed. MitoGel™ is a combination of mitomycin C with RTGel™, a reverse-thermal hydrogel composed of a combination of polymers that allows it to exist as a liquid at cold temperatures but solidify to a gel state at body temperature.¹⁰ This product was developed to address the constraints of the upper urinary tract, where continuous urine production and ureteral peristalsis prevents drug retention (when in liquid form) in the upper tract. The hypothesis for MitoGel™ is that upon delivery to the upper urinary tract, it would gelatinize and urine would produce a slow dissolution of the gel, allowing a sustained release of mitomycin C into the upper tract allowing prolonged exposure to the urothelium.

In a preclinical swine animal model, MitoGel™ remained visible in the upper urinary tract for four to six hours on fluoroscopic and computed tomographic assessment following antegrade instillation.¹⁰ Further, there was no evidence that this approach caused urinary obstruction, acute kidney injury, sepsis, or myelosuppression. These safety results were confirmed in a study assessing six once-weekly unilateral retrograde instillations of Mitogel™.¹¹

Up until May 2018, Knoedler and Raman highlighted that there had been no significant advances in the topical treatment of patients with upper tract urothelial carcinoma over the past two decades.¹² However, on December 19, 2019, UroGen Pharma Ltd. announced that the U.S. Food and Drug Administration had accepted filing and granted priority review for the New Drug Application for UGN-101. As of April 15, 2020, the United States Food and Drug Administration approved mitomycin (JELMYTO™) for the treatment of patients with low-grade upper tract urothelial cancer based on pre-publication results from the OLYMPUS Phase III study (NCT02793128). This represents the first agent specifically approved for this approach and indication.

OLYMPUS

While preliminary data for UGN-101 were presented by Dr. Lerner at the American Urological Association 2019 Annual Meeting in Chicago, the final results were published in Lancet Oncology on April 29, 2020. The remainder of this article will discuss this publication and contextualize the results.

OLYMPUS is a Phase III, open-label, single-arm trial designed to assess the efficacy, safety, and tolerability of UGN-101 in patients with low grade, noninvasive upper tract urothelial cancer. Patients were accrued at 24 academic sites in the United States and Israel. Eligible patients were adults (18 years of age or older) with either primary or recurrent biopsy-proven low-grade upper tract urothelial carcinoma of the renal pelvis or calyces, diagnosed in the two months prior to trial screening. Patients must have had a life expectancy of at least two years and adequate performance status (Eastern Cooperative Group performance status score less than 3 or Karnofsky Performance Status score of more than 40).

Importantly, patients must have had one or more low-grade lesions above the ureteropelvic junction measuring 5-15 millimeters in greatest dimension. Patients with lesions larger than this were eligible if they underwent “downsizing” via endoscopic treatment prior to initiation of treatment.

Patients with ureteral tumors or lower urinary tract (i.e. bladder) tumors were excluded unless these were completely endoscopically treated before starting treatment. Similarly, patients with bilateral tumors were eligible for inclusion only if one renal unit was removed (via radical nephroureterectomy) or completely endoscopically treated. Patients who received BCG in the six months prior to the start of the study (visit 1) were excluded, as were patients receiving systemic or intravesical chemotherapy.

The determination of resectability was made at baseline by enrolling surgeons with unresectable tumors typically due to difficult access to the lower pole of the kidney.

Additionally, patients were required to have adequate hematologic, hepatic, and renal function as evidenced by routine laboratory testing (WBC ≥ 3000 cells per µL, ANC ≥ 1500 cells per µL, platelets ≥ 100,000 per µL, hemoglobin ≥ 9.0 mg/dL, total bilirubin ≤ 1.5 x the upper limit of normal; aspartate aminotransferase and alanine aminotransferase ≤ 2.5 x the upper limit of normal, alkaline phosphatase ≤ 2.5 x the upper limit of normal, and estimated glomerular filtration rate ≥ 30 mL/min.

Enrolled patients received six once-weekly instillations of UGN-101 as an induction course. This was administered via retrograde instillation with ureteral catheterization. The volume of UGN-101 administered was determined using the average of three fluoroscopic assessments of renal pelvic and calyceal volume. Notably, UGN-101 treatment was administered in a variety of settings including clinics, outpatient surgical centers, and operating rooms with both general and local anesthesia based on individual surgeon preference (nearly three quarters received local anesthesia or sedation without general anesthesia). Treatment was deferred among patients experiencing adverse events.

Four to six weeks following initial treatment, patients received their primary disease evaluation including ureteroscopy, selective upper tract cytology, and for-cause biopsy where indicated. Complete response was defined as a negative endoscopic evaluation and the absence of histologic or cytologic evidence of disease.

Patients who experienced a complete response were then offered ongoing monthly maintenance is offered for 11 instillations or until the first recurrence. Durability was assessed at 3-, 6-, 9-, and 12-months following initial treatment.

Among 110 patients screening, 74 were enrolled and 71 patients received treatment. As expected given the demographics of upper tract urothelial carcinoma, patients were predominately male with a median age of 71 years. The vast majority (87%) were white and 79% were current or former smokers. While 89% had two renal units at the time of enrollment, 11% had only a single unit due to congenital or therapeutic reasons. 30% of patients had a history of previous TURBT for bladder cancer and 52% of patients had previous renal ablative surgeries. Thus, in total, 87% of patients had undergone prior surgery for urothelial carcinoma.

At baseline enrollment, most patients had multifocal disease with a median of two lesions (range 1 to 8). Prior to endoscopic debulking, the median diameter of the papillary tumor was 14 millimeters (range 5 to 50 millimeters). Median total tumor burden, calculated as the sum of the largest diameters of each lesion, was 17 millimeters (range 5 to 65 millimeters). Notably, 34 patients (48%) had a tumor that was deemed unresectable based on being unreachable by laser.

Of the 71 patients who received at least one dose of the study medication, 61 completed the six treatments defining the initial treatment. Among those who discontinued treated, this was due to adverse events in nine patients and personal reasons in the remaining one.

Among the 71 patients who received at least one dose, 42 patients (59%, 95% confidence interval [CI] 47-71%) had a complete response at the time of primary disease evaluation. Of the remainder, eight (11%) had a partial response, 12 (17%) had no response, six (8%) had newly diagnosed high-grade disease, and three (4%) had an indeterminate response. The central histologic and cytologic evaluation led to similar complete response results (37 of 59, 63%).

Of the 42 patients with complete response, 41 entered follow-up. Of these, 29 (71%) received at least one dose of maintenance therapy and six (15%) were continuing on maintenance therapy at the time of data cut-off. Of the 23 patients who started but were no longer receiving maintenance therapy, reasons for discontinuation included adverse events in 10 patients, investigator discretion in 10 patients, patient non-compliance with the treatment regime in five patients, tumor recurrence in two patients, and logistical considerations in one patient.

Twelve-month durability could be assessed in 20 patients. Of these 20 patients, 14 (70%) showed ongoing durability of their complete response and six had a documented recurrence during follow-up. However, none of these patients progressed to high-grade or invasive disease. Among those with a complete response at primary disease evaluation, 84% (95% CI 71-97%) remained disease-free at 12 months. The median time to recurrence was reported as 13 months (95% CI 13 months to not estimable) though should be considered highly tenuous given six patients at risk at 12 months and one patient at risk at 13 months.

Subgroup analyses demonstrated stability of effect across patient demographics (age, gender, and body mass index), tumor characteristics (number of lesions before and after debulking, size of lesions before and after debulking, total tumor burden before and after debulking, tumor resectability), number of treatments received at initial induction (six or less than six), prior treatments for urothelial carcinoma, and prior treatments for upper tract urothelial carcinoma.

Despite these promising results, toxicity was not insignificant: 67 patients (94%) experienced adverse events, and 26 (37%) patients experienced severe adverse events. Sixty patients (85%) had adverse events that were deemed treatment-related and 19 (27%) had severe treatment-related events. Nineteen patients (27%) discontinued treatment due to adverse events both in the initial six-week treatment period (nine patients, 13%) and during maintenance (10 patients, 14%). Among adverse events of particular interest, renal functional impairment was noted in 14 patients (20%). There was also a significant burden of urinary tract morbidity: among 71 patients who received at least one dose of study medication, 48 patients (68%) had an adverse event related to the urinary system including 11 (23%) who did not require surgical intervention, 24 (50%) who required transient stent placement, 11 (23%) who required long-term stent placement (still in place at the time of data cut-off), and two (4%) who required nephroureterectomy due to the need for permanent drainage as a result of ureteral stenosis.

Conclusions

Radical nephroureterectomy, despite being the historical gold standard for patients with upper tract urothelial carcinoma, results in renal functional impairment as significant oncologic overtreatment in many patients with low-grade disease. However, endoscopic management of upper tract urothelial cancer, while technically feasible and offering a nephron-sparing approach, is associated with high rates of recurrence and non-insignificant rates of progression necessitating radical surgical treatment. Further, a significant proportion of tumors will be unresectable ureteroscopically due to anatomic location. Intra-luminal therapy is a mainstay in the treatment of non-muscle invasive bladder cancer but has not been widely used in patients with upper tract disease. The recently published Phase III OLYMPUS trial demonstrates both the feasibility of treatment with UGN-101, a unique hybrid of mitomycin-C and RTGel™, and promising oncologic outcomes. However, treatment with UGN-101 was associated with significant urinary tract morbidity.

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

Published Date: May 2020

Related Content:
Watch: Nephron-Sparing Management of Low-Grade UTUC with UGN-101 (Mitomycin Gel) for Instillation: The Olympus Trial Experience - Seth Lerner

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.

Since the beginning of the COVID-19 pandemic in early 2020, the diagnosis, treatment and surveillance of cancer has been transformed globally. The heavy demand for resources, exacerbated by limited excess health system capacity, means that health care systems have become quickly overwhelmed and hospitals have become sources for virus transmission.

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.

Upper tract urothelial carcinoma accounts for only 5-10% of urothelial carcinoma, with an annual incidence of two cases per 100,000 people in Western countries.¹ Approximately 60% of upper tract urothelial carcinomas are invasive at diagnosis, with a peak incidence in people 70-90 years of age and more commonly diagnosed in males.^1,2 Upper tract urothelial carcinoma commonly presents with hematuria, and computed tomography urography has the highest diagnostic accuracy for diagnosis with a sensitivity of 0.67-1.0 and specificity of 0.93-0.99.³ Additionally, urine cytology and ureteroscopy may also play an important role in the diagnosis and initial workup of upper tract urothelial carcinoma.

Over the last several months, the diagnosis, treatment, and surveillance of genitourinary malignancies has been transformed by the global COVID-19 pandemic. The heavy demand for resources, exacerbated by limited excess health system capacity, means that health care systems have become quickly overwhelmed and hospitals have become sources for virus transmission. Furthermore, a severe COVID-19 phenotype is seen more commonly in men and older, more comorbid patients.⁴ Indeed, this is the same comorbidity profile common for patients with upper tract urothelial carcinoma. Early results from the Lombardy region of Italy showed that among 1,591 patients admitted to the ICU, the median age was 63 years (IQR 56-70) and 82% were male. Among these patients, the mortality rate was 26%, which is likely to increase with additional follow-up.⁵


As clinicians, it is important to be good stewards of resources, patient safety, and community health initiatives, but at the same time prioritize oncology patients for whom delays in treatment may result in harm. The management of upper tract urothelial carcinoma is typically directed by a combination of disease grade (low vs high) and patient comorbidity. 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 upper tract urothelial carcinoma, providing recommendations as to who can safely defer treatment until after the pandemic is over versus those that should be treated without delay.

Management of Low-Risk Upper Tract Urothelial Carcinoma

Numerous studies have demonstrated that a period of endoscopic management of low-grade upper tract urothelial carcinoma is safe.¹ In fact, kidney-sparing surgery is recommended by the European Association of Urology guidelines for patients with low-risk upper tract urothelial carcinoma regardless of the status of the contralateral kidney.¹ According to the guidelines, low-risk disease includes having all of the following factors: (i) unifocal disease, (ii) tumor size <2 cm, (iii) low-grade cytology, (iv) low-grade ureteroscopic biopsy, and (v) no invasive findings on CT-urogram.¹ In the stratification of resources during this time of the COVID-19 pandemic, a delay in treatment (i.e. laser ablation, UGN-101, etc.) and surveillance (i.e. either imaging and/or ureteroscopic surveillance) of low-risk (low-grade) upper tract urothelial carcinoma is advocated.

The Impact of Delayed Radical Nephroureterectomy

The impact of delayed radical nephroureterectomy for those requiring a more aggressive intervention is less clear. Several studies have assessed the impact of delaying radical nephroureterectomy for diagnostic ureteroscopy +/- biopsy. In patients eventually undergoing radical nephroureterectomy, single-center studies have shown that delays to surgery due to ureteroscopy beforehand did not affect survival in cohorts of patients with predominately low-grade disease (high-grade comprising approximately one-third of cohort) or mixed disease characteristics (high-grade comprising approximately 50% of cohort), though undergoing two ureteroscopic treatments prior to radical nephroureterectomy was associated with an increased risk of intravesical recurrence in patients with predominately high-grade disease (high-grade comprising approximately 70% of cohort).⁶

Nison et al. utilized the French Collaborative National Database on upper urinary tract urothelial carcinoma (UUT-UC) to evaluate the influence of ureteroscopy prior to radical nephroureterectomy on cancer-specific survival, (CSS), recurrence-free survival (RFS), and metastasis-free survival (MFS).⁷ This study had 512 patients with nonmetastatic upper tract urothelial carcinoma between 1995 and 2011, of which 170 patients underwent ureteroscopy prior to radical nephroureterectomy and 342 did not undergo ureteroscopy (immediate radical nephroureterectomy). As expected, time from diagnosis to radical nephroureterectomy was longer among patients undergoing ureteroscopy (79.5 vs 44.5 days, p=0.04). However, there were no differences in five-year CSS (p=0.23), RFS (p=0.89), or MFS (p=0.35), even in a subset of patients with confirmed muscle-invasive disease (CSS p=0.21; RFS p=0.44; MFS p=0.67). Taken together, despite an increased time to radical nephroureterectomy, these studies suggest that diagnostic ureteroscopy can be performed for the complete workup of a patient with upper tract urothelial carcinoma without affecting oncologic outcomes. Further, these studies show no harm to a delay of approximately five weeks.

Two institutional studies have assessed the impact of delayed radical nephroureterectomy on pathologic and survival outcomes, both using a three-month threshold. Waldert et al.⁸ assessed the impact of radical nephroureterectomy ≥3 months after diagnosis among 41 patients (median time to radical nephroureterectomy 110 days, range 93-137) compared to 146 patients undergoing radical nephroureterectomy <3 months (median time to radical nephroureterectomy 33 days, range 3-89) from diagnosis. Patients waiting ≥3 months had no differences in risk of disease recurrence (p=0.066) and cancer-specific mortality (p=0.153), but did have higher risk of pathological features including worse pathologic stage (p=0.044), lymph node involvement (n=0.002), lymphovascular invasion (p=0.010), tumor necrosis (p=0.026), and infiltrative tumor architectures (p=0.039).⁸ Sundi et al. performed a similar analysis among patients at the M.D. Anderson Cancer Center. ⁹ This study had 186 patients that underwent early surgery (<3 months after diagnosis) and 54 patients that underwent delayed surgery (≥3 months after diagnosis). They also found no difference in five-year CSS rates (71% vs 72%, p=0.39) or OS rates (69% vs 60%, p=0.69) for patients treated ≥3 months or <3 months from diagnosis, respectively.⁹ The most common factor leading to a delay in surgery was the administration of neoadjuvant chemotherapy, which did not impact survival.

At the population level, Xia et al.¹⁰ used the National Cancer Database to assess the impact of surgical wait times on survival among patients with upper tract urothelial carcinoma. A total of 3,581 patients were stratified into six groups based on surgical wait time: ≤ 7 days (n=230), 8 to 30 days (n=1,398), 31 to 60 days (n=1,250), 61 to 90 days (n=472), 91 to 120 days (n=143), and 121 to 180 days (n=88). There was no difference in OS for those undergoing radical nephroureterectomy at 31 to 60 days, 61 to 90 days, and 91 to 120 days, compared to 8 to 30 days, after diagnosis among this cohort of predominately high-risk disease (66.9% of patients had high-risk disease (high grade or ≥pT2)). However, those with a delay of 121 to 180 days had worse OS in the overall cohort (vs 8 to 30 days; hazard ratio [HR] 1.61, 95% confidence interval [CI] 1.19-2.19), as well as in the high-risk cohort (HR 1.56, 95% CI 1.11-2.20).

From the available literature, adequate workup of upper tract urothelial carcinoma often includes ureteroscopic visual and/or biopsy confirmation, which may slightly delay radical nephroureterectomy with no apparent effect on outcomes. Furthermore, institutional and population-level data suggest that there may be worse pathological outcomes with delays in radical nephroureterectomy for more than three months, however with little to no impact on survival outcomes. During the COVID-19 pandemic, it is likely reasonable to delay radical nephroureterectomy for a period of time (ie. <3 months) and prioritize operations for those with symptomatic or high-grade/volume disease on a case-by-case basis.

Systemic Therapy for Upper Tract Urothelial Carcinoma During COVID-19

Locally advanced and metastatic upper tract urothelial carcinoma is historically associated with a poor prognosis. These patients and their physicians must weigh the risk of delayed treatment on cancer prognosis versus the inherent risk of COVID-19 infection, particularly for those in an immunocompromised state.

The POUT trial, published in March 2020 in the Lancet,¹¹ changed the landscape of perioperative chemotherapy for patients having previously undergone a radical nephroureterectomy with pT2–pT4, pN_any or pT_any, pN1–3M0 disease. In this trial, 129 patients were randomized to surveillance and 132 to adjuvant chemotherapy. The median follow-up was 30.3 months (IQR 18.0-47.5 months). There were 60 (47%) disease-free survival (DFS) events in the surveillance cohort and 35 (27%) in the chemotherapy cohort; as such, the unadjusted HR was 0.45 (95% CI 0.30-0.68) in favor of chemotherapy (log-rank p = 0.0001). The three-year DFS rate was 46% for surveillance (95% CI 36-56) and 71% for chemotherapy (95% CI 61-78). MFS also favored chemotherapy, with an HR of 0.48 (95% CI 0.31-0.74, log-rank p = 0.0007), and the three-year event-free rates were 53% (95% CI 42-63) for those on surveillance and 71% (95% CI 60-79) for those receiving chemotherapy. Based on these results, adjuvant chemotherapy is now regarded by many to be standard of care. Looking closer at the methodology, protocol-specific recommendations were for chemotherapy to begin within 90 days of radical nephroureterectomy. Although the trial does not report granular timing of chemotherapy within the 90-day window, during the COVID-19 pandemic it would seem reasonable that appropriate adjuvant chemotherapy could be delayed up to the 90-day (three-month) time period without a significant impact on DFS events.

For patients with metastatic disease, there is guidance to the management of systemic therapy provided in a recent manuscript from Gillessen-Sommer and Powles.¹² For patients with urothelial cancer (bladder vs upper tract not specified), the following recommendations are provided:

• First-line treatment for metastatic disease should be commenced where possible
• Chemotherapy in platinum-refractory disease and perioperative chemotherapy for operable disease should not be commenced without justification
• Treatment for front-line metastatic disease should not be stopped without justification
• Chemotherapy for platinum-refractory patients who are not responding to therapy and more than three chemotherapy cycles in the perioperative setting can potentially be stopped or delayed after careful consideration
• Immune checkpoint inhibitors, rather than chemotherapy in PD-L1-positive frontline metastatic disease, can be given preferentially compared to other options

Conclusions

The management of upper tract urothelial carcinoma depends on grade and stage of the tumor, which does not change during the COVID-19 pandemic. Patients with low-grade tumors can safely defer treatment, whereas patients requiring a radical nephroureterectomy can likely delay surgery for up to three months with minimal/no impact in survival outcomes. Patients that are candidates for adjuvant chemotherapy after radical nephroureterectomy can likely defer treatment up to three months given the 90-day treatment window for chemotherapy in the POUT trial. For those with metastatic disease, front-line treatment should commence if possible, and immune checkpoint inhibitor therapy should be reserved for only those with PD-L1-positive tumors.

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

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