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, pNany or pTany, 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
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; Christopher J.D. Wallis, MD, PhD, Urology Resident and Epidemiologist, University of Toronto, Toronto, Ontario