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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.

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

Background

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

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

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 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

June 26, 2020, marked the 20^th anniversary of the publication of the first working draft from the Human Genome Project. At a special White House event to commemorate the results of this 10-year public effort (it was really more like 50 years since the discovery of DNA, but I digress), then-President Bill Clinton called the project “the most wondrous map ever created by humankind”, and touted its promise to detect, prevent, and treat disease.  Obtaining that first sequence from one human cost about $2B and resulted from a massive global public/private partnership.

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.