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Upper Tract Urothelial Carcinoma

The Current Landscape of Neoadjuvant Therapy in Patients with Upper Tract Urothelial Carcinoma

Introduction

Urothelial carcinoma of the upper tract accounts for only five to ten percent of all urothelial carcinomas,1 with an estimated annual incidence in Western countries of almost two cases per 100,000 inhabitants.2 Approximately two-thirds of patients with de novo upper tract urothelial carcinoma present with invasive disease at diagnosis,3 likely owing to the absence of a muscularis propria layer in the upper tracts. Large series have reported five-year cancer-specific mortality rates of 30% for muscle-invasive, organ-confined tumors and 56% for locally advanced tumors.4

Written by: Rashid K. Sayyid, MD, MSc, and Zachary Klaassen, MD, MSc
References:
  1. Babjuk, M, Burger M, Capoun O, et al. EAU Guidelines on Non-muscle-invasive Bladder Cancer (T1, T1 and CIS), in EAU Guidelines, Edn. presented at the 37th EAU Annual Congress Amsterdam. 2022, EAU Guidelines Office, Arnhem, The Netherlands.
  2. Siegel, RL, Miller KD, Fuchs HE, Jemal A. Cancer Statistics, 2021. CA Cancer J Clin 2021;71(1):7-33.
  3. Margulis V, Shariat SF, Matin SF, et al. Outcomes of radical nephroureterectomy: a series from the Upper Tract Urothelial Carcinoma Collaboration. Cancer 2009;115(6):1224-33.
  4. van Doeveren T, van der Mark M, van Leeuwen PJ, et al. Rising incidence rates and unaltered survival rates for primary upper urinary tract urothelial carcinoma: a Dutch population-based study from 1993 to 2017. BJU Int 2021; 128(3): 343-51.
  5. Collà Ruvolo C, Nocera L, Stolzenbach LF, et al.. Tumor Size Predicts Muscle-invasive and Non-organ-confined Disease in Upper Tract Urothelial Carcinoma at Radical Nephroureterectomy. Eur Urol Focus 2022;8(2):498-505.
  6. Birtle A, Johnson M, Chester J, et al. Adjuvant chemotherapy in upper tract urothelial carcinoma (the POUT trial): a phase 3, open-label, randomised controlled trial. Lancet 2020;395(10232):1268-77.
  7. Advanced Bladder Cancer Meta-analysis Collaboration. Neoadjuvant chemotherapy in invasive bladder cancer: update of a systematic review and meta-analysis of individual patient data advanced bladder cancer (ABC) meta-analysis collaboration. Eur Urol 2005;48(2):202-5.
  8. Hoffman-Censits JH, Trabulsi EJ, Chen DYT, et al. Neoadjuvant accelerated methotrexate, vinblastine, doxorubicin, and cisplatin (AMVAC) in patients with high-grade upper-tract urothelial carcinoma. J Clin Oncol 2014;32(4):Suppl.
  9. Margulis V, Puligandla M, Trabulsi EJ, et al. Phase II Trial of Neoadjuvant Systemic Chemotherapy Followed by Extirpative Surgery for Patients with High Grade Upper Tract Urothelial Carcinoma. J Urol 2020;203(4):690-8.
  10. Coleman JA, Yip W, Wong NC, et al. Multicenter Phase II Clinical Trial of Gemcitabine and Cisplatin as Neoadjuvant Chemotherapy for Patients With High-Grade Upper Tract Urothelial Carcinoma. J Clin Oncol 2023;JCO2200763.
  11. Basile G, Banidin M, Gibb EA, et al. Neoadjuvant Pembrolizumab and Radical Cystectomy in Patients with Muscle-Invasive Urothelial Bladder Cancer: 3-Year Median Follow-Up Update of PURE-01 Trial. Clin Cancer Res 2022;28(23):5107-14.

After POUT: Implications of Perioperative Chemotherapy for Upper Tract Urothelial Carcinoma

Before the POUT Trial

Before the POUT trial, the largest randomized Phase III trial assessing perioperative chemotherapy for locally advanced UTUC, decisions in management relied primarily on retrospective studies and expert opinion. Furthermore, the data from these studies are conflicting regarding the efficacy of perioperative chemotherapy. In 2009, Hellenthal and colleagues5 used an international collaborative database to assess the utilization and outcomes of adjuvant chemotherapy after radical nephroureterectomy in patients with UTUC. They identified 1,390 patients who underwent nephroureterectomy for nonmetastatic UTUC between 1992 and 2006. Of these cases, 39% were classified as high-risk (pT3N0, pT4N0 and/or lymph node-positive). For the analysis, these patients were divided into two groups, including those who did and did not receive adjuvant chemotherapy, and stratified by gender, age group, performance status, and tumor grade and stage. Among the 542 high-risk patients, 22% received adjuvant chemotherapy, which was more commonly administered in the context of increased tumor grade and stage (p <0.001). The median survival for the entire cohort was 24 months (range 0 to 231 months), and there was no significant difference in all-cause death (chemotherapy vs none: hazard ratio [HR] 1.06, 95% confidence interval [CI] 0.80-1.40) or cancer-specific death (chemotherapy vs none: HR 1.26, 95% CI 0.93-1.71) between patients who did and did not receive adjuvant chemotherapy.

A subsequent study from the European Association of Urology – Young Academic Urologists and the Upper Tract Urothelial Collaboration also assessed adjuvant chemotherapy after radical nephroureterectomy.6 This study collated data from 15 centers (1,544 patients) between 2000 and 2015; patients were required to have pT2-4N0/Nx or N+ disease and had undergone a radical nephroureterectomy. The primary analysis used 1:1 propensity score matching, with inverse probability of treatment weighting with a primary endpoint of overall survival (OS). Among the 1,544 patients included, 312 received adjuvant chemotherapy and 1,232 underwent observation. In the matched analysis, there was no difference observed in OS between adjuvant chemotherapy and observation (HR 1.14, 95% CI 0.91-1.43; P = 0.268). Furthermore, a six‐month landmark analysis demonstrated little impact of early events on the treatment effect on OS, with an HR of 1.28 (95% CI 1.00–1.64; p = 0.051).

In contrast to these two studies that failed to demonstrate a benefit to adjuvant chemotherapy, a systematic review and meta-analysis published in 2014 assessed the role of adjuvant and neoadjuvant chemotherapy for patients with UTUC.7 Not surprisingly, this systematic review found no randomized trials investigated the role of adjuvant chemotherapy for UTUC. There was one prospective study comprising 36 patients that investigated adjuvant carboplatin-paclitaxel. Furthermore, there were nine retrospective studies (totaling 482 patients) among patients receiving cisplatin-based or non-cisplatin-based adjuvant chemotherapy after nephroureterectomy compared to 1,300 patients receiving nephroureterectomy alone. Across the three cisplatin-based studies, the pooled hazard ratio for OS was 0.43 (95% CI, 0.21-0.89; p=0.023) favoring adjuvant cisplatin compared with those who received surgery alone. For disease-free survival (DFS), the pooled HR across two studies was 0.49 (95% CI, 0.24-0.99; p=0.048) favoring adjuvant cisplatin. Among the non-cisplatin-based chemotherapy studies, there was no benefit for neoadjuvant chemotherapy. For the neoadjuvant chemotherapy section of the systematic review, the authors identified two Phase II trials that demonstrated favorable pathologic downstaging rates (60%-75% downstaging to ≤pT1N0). Across two retrospective studies investigating neoadjuvant chemotherapy, there was a disease-specific survival (DSS) benefit for neoadjuvant chemotherapy, with a pooled HR of 0.41 (95% CI, 0.22-0.76; p=0.005).


The POUT Trial

The POUT trial was a Phase III, parallel group, open-label, randomized controlled trial done at 71 National Health Service (NHS) hospitals in the United Kingdom.8 Eligible patients were ≥16 years, had received a radical nephroureterectomy for UTUC, were postoperatively staged with either muscle-invasive (pT2–pT4, pNany) or lymph node-positive (pTany, pN1–3) M0 disease with predominantly transitional cell carcinoma histology, and were fit to receive adjuvant chemotherapy within 90 days of surgery. Patients also had to have a glomerular filtration rate (GFR) of ≥30 mL/min. Prespecified stratification factors included platinum chemotherapy agent (cisplatin vs carboplatin), preoperative radiologically or pathologically assessed nodal involvement (N0 vs N1 vs N2 vs N3), the status of surgical margins (positive vs negative), and treatment center. Patients were randomized 1:1 to receive either surveillance or adjuvant chemotherapy: four 21-day cycles of platinum-based chemotherapy (cisplatin 70 mg/m2) within 14 days of randomization; gemcitabine (1000 mg/m2) given on days one and eight of each cycle. Patients with impaired renal function (GFR ≥30 mL/min and <50 mL/min) received carboplatin rather than cisplatin.

Patients were followed at 3, 6, 9, and 12 months, then every 6 months to 36 months from randomization, and annually thereafter. The radiographic assessment included a CT of the thorax, abdomen, and pelvis at 3, 6, 9, 12, 18, 24, 30, and 36 months, then annually to 60 months. Cystoscopy was done every 6 months to 24 months, then annually up to 60 months after surgery. Toxicity was assessed by CTCAE v4.  Furthermore, this was the first trial in UTUC to collect patient-reported outcomes: patients filled out the EORTC quality-of-life of cancer patients questionnaire (QLQ-C30) and the EuroQol five dimensions five levels questionnaire (EQ-5D-5L) at baseline and before cycle three and at 3, 6, 12, and 24 months after randomization. The primary endpoint of this trial was DFS defined as time from randomization to either first recurrence in the tumor bed, first metastasis, or death from any cause. Secondary endpoints included metastasis-free survival (MFS), OS, treatment compliance, acute toxicity, late toxicity, and patient-reported quality of life. The trial was powered to detect a hazard ratio of 0.65 (i.e. improvement in three-year DFS from 40% to 55%; 2-sided alpha = 5%, 80% power) with Peto-Haybittle (p<0.001) early stopping rules for efficacy and inefficacy.

There were 261 patients included in the trial between June 19, 2012 and November 8, 2017 at 57 of the 71 participating centers in the UK, including 129 patients randomized to surveillance and 132 to chemotherapy; 260 patients were included in the intention to treat analysis. In October 2017, the independent trial oversight committees recommended POUT close to recruitment as data collected to date met the early stopping rule for efficacy. Included patients were a median 68.5 years of age (IQR 62.0-74.1 years). With respect to tumor characteristics, 94% of patients had pT2-T3 disease and 91% were N0. The median follow-up was 30.3 months (IQR 18.0-47.5 months). There were 7 of 131 patients allocated to chemotherapy that did not start treatment and 75% of those that started chemotherapy received four cycles. There were 60 (47%) 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. Currently, there have been 62 deaths recorded (38 for surveillance, 24 for chemotherapy) and the OS analysis is planned for when 88 deaths occur, or all patients have ≥2 years of follow-up.

Grade ≥3 toxicities were reported in 44% of chemotherapy patients and 4% surveillance patients (p < 0.0001). During the treatment period, the most common grade ≥3 toxicities in chemotherapy patients were neutropenia (36%) and thrombocytopenia (10%). Analysis of late toxicity is planned after a two-year follow-up of all patients. Quality of life questionnaires were returned by 95% of patients at baseline (95% of those allocated to surveillance and 95% of those allocated to chemotherapy), 82% at three months (81% of those allocated to surveillance and 82% of those allocated to chemotherapy), and 70% at 12 months (70% of those allocated to surveillance and 70% of those allocated to chemotherapy). The mean overall global health status score at baseline was 77% (standard deviation 19) for the chemotherapy group and 76% (standard deviation 19) for the surveillance group. Subsequently, the overall global health status was lower during chemotherapy (before cycle 3) and immediately afterward (at three months) in participants allocated chemotherapy versus surveillance, however the difference resolved by six months of follow-up.

Implications and Future Considerations Following the POUT Trial

Given the rarity of UTUC and the clinical equipoise for conducting a perioperative chemotherapy trial in this disease state, the trialist and the patients involved in this study are to be congratulated for completing this important Phase III trial. As has been discussed amongst thought leaders in the field and summarized in a discussion between Dr. Ashish Kamat and trial lead Dr. Alison Birtle, this is practice-changing data: all patients with locally advanced UTUC after radical nephrectomy should be considered for receipt of adjuvant cisplatin-based chemotherapy.

There are several important considerations as we move into the post-POUT trial era of treating locally advanced UTUC. First, patients with adequate renal function should receive the combination of cisplatin-gemcitabine adjuvant chemotherapy. Typically, a GFR of <60 mL/min is deemed “cisplatin-ineligible”, however, the POUT trial included patients with GFRs as low as 50 mL/min, which is standard practice in the UK. However, even for those with a GFR < 50 mL/min that received the combination of carboplatin-gemcitabine (n=96), there was still a non-significant DFS benefit (HR 0.66, 95% CI 0.35-1.26).8 As such, essentially all pT2–pT4, Nany or pTany, N1–3M0 patients should be considered for an adjuvant chemotherapy regimen that fits their performance status and post-radical nephroureterectomy renal function profile.

Second, the argument for adjuvant chemotherapy as standard of care should only grow stronger as the data matures. Indeed, the benefit of adjuvant chemotherapy was based on DFS and MFS benefit, however with such strong hazard ratios favoring chemotherapy vs surveillance (DFS HR 0.45; MFS HR 0.48) there likely will be a survival benefit with longer follow-up. Furthermore, early survival data reported in the POUT publication favor chemotherapy vs surveillance (38 deaths in surveillance arm; 24 deaths in chemotherapy arm). As such, there is a signal for a more than likely survival benefit based on DFS/MFS benefit and early survival data.

Third, as POUT has demonstrated a survival benefit to perioperative chemotherapy in the adjuvant setting it has re-raised questions regarding the role of neoadjuvant therapy. As nephroureterectomy removes a significant nephron mass, neoadjuvant administration would allow more patients to receive cisplatin, which is known to be more efficacious than carboplatin. However, this must be balanced against issues of poor pre-operative staging in UTUC. Unlike bladder cancer in which TURBT fairly reliably can distinguish superficial from muscle-invasive disease, this distinction is much more difficult in UTUC. Certainly, in patients with obvious invasive disease based on axial imaging and marginal renal function, extrapolation from POUT would suggest that neoadjuvant chemotherapy may be a rational approach.

Finally, the question remains as to how immunotherapy fits into the picture given the POUT data. There are currently no Phase III trials underway to address the role of immunotherapy in the adjuvant treatment of UTUC alone, however, ongoing trials assessing pembrolizumab (Neoadjuvant Pembrolizumab in Combination with Gemcitabine Therapy in Cis-eligible/Ineligible Urothelial Carcinoma Patients) in the perioperative setting for bladder urothelial carcinoma have preplanned subgroup analyses for patients with UTUC. Atezolizumab has shown real-world efficacy in metastatic UTUC, as evaluated in the SAUL study (22% included had UTUC)9, however, what role immunotherapy plays in the perioperative setting for UTUC remains to fully elucidated.

Written by: Zachary Klaassen, MD, MSc
References: 1. Rouprêt, Morgan, Marko Babjuk, Eva Compérat, Richard Zigeuner, Richard J. Sylvester, Maximilian Burger, Nigel C. Cowan et al. "European association of urology guidelines on upper urinary tract urothelial carcinoma: 2017 update." European urology 73, no. 1 (2018): 111-122.
2. Sternberg, Cora N., Iwona Skoneczna, J. Martijn Kerst, Peter Albers, Sophie D. Fossa, Mads Agerbaek, Herlinde Dumez et al. "Immediate versus deferred chemotherapy after radical cystectomy in patients with pT3–pT4 or N+ M0 urothelial carcinoma of the bladder (EORTC 30994): an intergroup, open-label, randomised phase 3 trial." The lancet oncology 16, no. 1 (2015): 76-86.
3. of Trialists, International Collaboration. "International phase III trial assessing neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: long-term results of the BA06 30894 trial." Journal of Clinical Oncology 29, no. 16 (2011): 2171.
4. Vale, C. A. "Advanced Bladder Cancer (ABC). Meta-analysis Collaboration. Adjuvant chemotherapy in invasive bladder cancer: a systematic review and meta-analysis of individual patient data." Eur Urol 48, no. 2 (2005): 189-199.
5. Hellenthal, Nicholas J., Shahrokh F. Shariat, Vitaly Margulis, Pierre I. Karakiewicz, Marco Roscigno, Christian Bolenz, Mesut Remzi et al. "Adjuvant chemotherapy for high risk upper tract urothelial carcinoma: results from the Upper Tract Urothelial Carcinoma Collaboration." The Journal of urology 182, no. 3 (2009): 900-906.
6. Necchi, Andrea, Salvatore Lo Vullo, Luigi Mariani, Marco Moschini, Kees Hendricksen, Michael Rink, Roman Sosnowski et al. "Adjuvant chemotherapy after radical nephroureterectomy does not improve survival in patients with upper tract urothelial carcinoma: a joint study by the European Association of Urology–Young Academic Urologists and the Upper Tract Urothelial Carcinoma Collaboration." BJU international 121, no. 2 (2018): 252-259.
7. Leow, Jeffrey J., William Martin-Doyle, Andre P. Fay, Toni K. Choueiri, Steven L. Chang, and Joaquim Bellmunt. "A systematic review and meta-analysis of adjuvant and neoadjuvant chemotherapy for upper tract urothelial carcinoma." European urology 66, no. 3 (2014): 529-541.
8. Birtle, Alison, Mark Johnson, John Chester, Robert Jones, David Dolling, Richard T. Bryan, Christopher Harris et al. "Adjuvant chemotherapy in upper tract urothelial carcinoma (the POUT trial): a phase 3, open-label, randomised controlled trial." The Lancet (2020).
9. Sternberg, Cora N., Yohann Loriot, Nicholas James, Ernest Choy, Daniel Castellano, Fernando Lopez-Rios, Giuseppe L. Banna et al. "Primary results from SAUL, a multinational single-arm safety study of atezolizumab therapy for locally advanced or metastatic urothelial or nonurothelial carcinoma of the urinary tract." European urology 76, no. 1 (2019): 73-81.

Upper Tract Urothelial Carcinoma: Updates in Local Treatment, Nephron Sparing Approaches, and Perioperative Chemotherapy

Upper tract urothelial carcinoma (UTUC) is a rare malignancy with an incidence of 1 case per 50,000 people in developed countries. Because symptoms are often non-specific, there are delays in presentation and diagnosis and, as a result, more than half of patients present with muscle-invasive or locally advanced disease.  The gold standard treatment for localized UTUC has been radical nephroureterectomy followed by surveillance.1 However, as with bladder urothelial carcinoma, UTUC has a range of primary tumor aggressiveness, ranging from relatively indolent, superficial low-grade disease to the aforementioned locally invasive disease. Thus, not all patients may require nephroureterectomy. Further, due to renal dysfunction or other medical comorbidities, patients may not be fit for radical surgery. 

Written by: Zachary Klaassen, MD, MSc
References:

1. Roupret M, Babjuk M, Comperat E, et al. European Association of Urology Guidelines on Upper Urinary Tract Urothelial Carcinoma: 2017 Update. European urology. 2018;73(1):111-122.
2. Petros FG, Li R, Matin SF. Endoscopic Approaches to Upper Tract Urothelial Carcinoma. Urol Clin North Am. 2018;45(2):267-286.
3. Samson P, Smith AD, Hoenig D, Okeke Z. Endoscopic Management of Upper Urinary Tract Urothelial Carcinoma. J Endourol. 2018;32(S1):S10-S16.
4. Cutress ML, Stewart GD, Zakikhani P, Phipps S, Thomas BG, Tolley DA. Ureteroscopic and percutaneous management of upper tract urothelial carcinoma (UTUC): systematic review. BJU Int. 2012;110(5):614-628.
5. Williams SK, Denton KJ, Minervini A, et al. Correlation of upper-tract cytology, retrograde pyelography, ureteroscopic appearance, and ureteroscopic biopsy with histologic examination of upper-tract transitional cell carcinoma. J Endourol. 2008;22(1):71-76.
6. Raman JD, Park R. Endoscopic management of upper-tract urothelial carcinoma. Expert Rev Anticancer Ther. 2017;17(6):545-554.
7. Grasso M, Fishman AI, Cohen J, Alexander B. Ureteroscopic and extirpative treatment of upper urinary tract urothelial carcinoma: a 15-year comprehensive review of 160 consecutive patients. BJU Int. 2012;110(11):1618-1626.
8. Motamedinia P, Keheila M, Leavitt DA, Rastinehad AR, Okeke Z, Smith AD. The Expanded Use of Percutaneous Resection for Upper Tract Urothelial Carcinoma: A 30-Year Comprehensive Experience. J Endourol. 2016;30(3):262-267.
9. Donin NM, Duarte S, Lenis AT, et al. Sustained-release Formulation of Mitomycin C to the Upper Urinary Tract Using a Thermosensitive Polymer: A Preclinical Study. Urology. 2017;99:270-277.
10. Knoedler JJ, Raman JD. Intracavitary therapies for upper tract urothelial carcinoma. Expert Rev Clin Pharmacol. 2018;11(5):487-493.
11. Birtle A, Johnson M, Chester J, et al. Adjuvant chemotherapy in upper tract urothelial carcinoma (the POUT trial): a phase 3, open-label, randomised controlled trial. Lancet. 2020. 
12. Sternberg CN, Skoneczna I, Kerst JM, et al. Immediate versus deferred chemotherapy after radical cystectomy in patients with pT3-pT4 or N+ M0 urothelial carcinoma of the bladder (EORTC 30994): an intergroup, open-label, randomised phase 3 trial. Lancet Oncol. 2015;16(1):76-86. 
13.International Collaboration of T, Medical Research Council Advanced Bladder Cancer Working P, European Organisation for R, et al. International phase III trial assessing neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: long-term results of the BA06 30894 trial. J Clin Oncol. 2011;29(16):2171-2177.
14. Advanced Bladder Cancer Meta-analysis C. Adjuvant chemotherapy in invasive bladder cancer: a systematic review and meta-analysis of individual patient data Advanced Bladder Cancer (ABC) Meta-analysis Collaboration. Eur Urol. 2005;48(2):189-199; discussion 199-201.
15. Birtle A, Chester J, Jones RJ, et al. Updated outcomes of POUT: A phase III randomized trial of peri-operative chemotherapy versus surveillance in upper tract urothelial cancer (UTUC). J Clin Oncol. 2021;39(no. 6_suppl):455-455.

Updates in Systemic Therapy for Upper Tract Urothelial Carcinoma: Perioperative Considerations

In this article, we will discuss data for the use of systemic therapy in upper tract urothelial carcinoma with a focus on perioperative systemic therapy.
Until recently, there have been very limited randomized data to guide the provision of perioperative systemic therapy in upper tract urothelial carcinoma. Thus, data has been extrapolated from patients with urothelial carcinoma of the bladder.

Neoadjuvant therapy

Data for the use of neoadjuvant chemotherapy prior to radical cystectomy in urothelial carcinoma of the bladder are robust: the Advanced Bladder Cancer meta-analysis collaboration, in a meta-analysis of 11 trials with 3,005 patients, demonstrated a significant survival benefit to the use of neoadjuvant platinum-based combination chemotherapy as compared to upfront surgery (hazard ratio 0.86, 95% confidence interval 0.77 to 0.95). In absolute terms, this corresponds to a 5% absolute survival at 5 years.5

In contrast, there is extremely limited data regarding the use of neoadjuvant chemotherapy in patients with upper tract urothelial carcinoma. No institution has published data on more than 50 patients who received neoadjuvant chemotherapy prior to nephroureterectomy. In two publications, the MD Anderson Cancer Center group has reported on their experience. Matin et al. reported on 43 patients with biopsy-proven high-grade upper tract urothelial carcinoma who underwent neoadjuvant chemotherapy prior to nephroureterectomy.6 They demonstrated a 14% pathologic complete response rate in this cohort. Additionally, when compared to historical controls, there was an increased likelihood of downstage (p=0.004): pT2 disease was found in 49% compared with 65% in controls and pT3 disease was found in 28% compared with 48%. In a more recent analysis, Porten et al. provided a retrospective review of 31 patients who underwent neoadjuvant chemotherapy prior to nephroureterectomy compared to 81 historical controls who received initial surgery for high-risk upper tract urothelial carcinoma.7 They demonstrated that patients receiving neoadjuvant chemotherapy had improved five year overall survival (80% versus 58%, p=0.02) and five year disease-specific survival (90% versus 58%, p=0.002). After adjusting for relevant patient, treatment and tumor characteristics, the risk of overall mortality (hazard ratio 0.42, p=0.035) and disease-specific mortality (hazard ratio 0.19, p=0.006) were significantly lower among patients who received neoadjuvant therapy.

More recently, Kubota and colleagues reported a multi-institutional analysis of 101 patients with high-risk upper tract urothelial carcinoma (stage cT3-4 or cN+) who received neoadjuvant chemotherapy prior to nephroureterectomy at 5 medical centers in Japan and compared these to 133 patients who received surgery alone.8 Most patients who received neoadjuvant chemotherapy in this cohort were given gemcitabine and carboplatin (75%) while a minority received gemcitabine and cisplatin (21%). The authors found that while neoadjuvant chemotherapy increased pathological downstaging and was independently predictive of improved recurrence-free survival and cancer-specific survival, they were unable to demonstrate improvements in overall survival.

Finally, in 2018, Liao et al reported their experience from Johns Hopkins.9 They compared 32 patients who received neoadjuvant chemotherapy prior to nephroureterectomy for biopsy-proven high-grade upper tract urothelial carcinoma to 208 patients who underwent surgery alone. These authors found a 9.4% pathologic complete response rate in addition to significant pathologic downstaging.

In comparison to the use of neoadjuvant chemotherapy for urothelial carcinoma of the bladder, there is potentially even greater rationale for its use in upper tract urothelial carcinoma. First, patients are much more likely to be able to tolerate a highly efficacious regime (gemcitabine and cisplatin) with two functioning kidneys prior to nephroureterectomy than they will post-operatively. Additionally, important prognostic information can be derived if patients experience pathological downstaging.1 However, one of the primary barriers to the use of neoadjuvant chemotherapy is the lack of reliable pre-operative pathologic specimens to identify invasive disease, as mentioned previously. Second, there are concerns regarding the delay to definitive surgical treatment, particularly in patients who may have chemoresistant disease. Third, there are concerns regarding a potential increase in perioperative morbidity.

Finally, there is a concern of overtreatment through the use of toxic medications in patients who may or may not have invasive disease. There have been attempts to assess the role of neoadjuvant chemotherapy in this patient population. A trial from the University of Michigan was terminated due to poor accrual (NCT01663285). Memorial Sloan Kettering is a sponsor for a trial of gemcitabine and cisplatin as neoadjuvant chemotherapy in patients with upper tract urothelial carcinoma, which according to the last update remains active but is no longer recruiting. This trial sought to enroll 57 participants in a Phase II design to assess the primary outcome of pathological response rate. Additionally, a Phase II ECOG-ACRIN trial seeking to assess pathologic complete response rates following neoadjuvant chemotherapy (MVAC or gemcitabine and cisplatin) among 36 patients with high-grade upper tract urothelial carcinoma. Results have not yet been published though they were presented at AUA 2018. While the gemcitabine and cisplatin arm did not meet accrual, 30 patients were accrued to the ddMVAC arm. Pathologic complete response was seen in 6 of 29 evaluable patients. None of these trials have provided a randomized comparison to surgery alone. In contrast, NCT02876861 is a trial from Xiangya Hospital of Central South University which is actively recruiting patients and randomizing to neoadjuvant chemotherapy with gemcitabine and cisplatin prior to nephroureterectomy or surgery alone. They are targeting accrual of 50 patients to assess the primary outcome of disease-free survival.

Adjuvant chemotherapy

Again, there is strong evidence for adjuvant chemotherapy in urothelial carcinoma of the bladder. In contrast to neoadjuvant chemotherapy, the data for adjuvant chemotherapy in upper tract urothelial carcinoma are more robust.

First, there is a meta-analysis of nine retrospective cohort studies comparing 482 patients who received adjuvant chemotherapy to 1,300 patients who were treated with surgery alone. Those who received adjuvant therapy had significantly improved disease-free survival (hazard ratio 0.49, 95% confidence interval 0.24 to 0.99) and overall survival (hazard ratio 0.43, 95% confidence interval 0.21 to 0.89)10. This analysis is limited by significant selection biases.

In contrast, a Phase III randomized trial of perioperative chemotherapy versus surveillance in upper tract urothelial cancer (POUT) is a Phase III, multicenter trial from the Institute of Cancer Research in the United Kingdom which randomized patients who are chemotherapy eligible with pT2-4, pN0-3 or pT1, pN+ following nephroureterectomy to adjuvant platinum-based chemotherapy or surveillance. The results of this trial remain to be published, although they have been presented at ASCO GU and EAU in 2018. To summarize, 123 patients were randomized to surveillance and 125 to adjuvant chemotherapy at 57 different centers. Patients in the intervention arm received either gemcitabine and cisplatin or gemcitabine and carboplatin as their renal function allowed. The majority of enrolled patients had pT3 disease (65%) and were node-negative (pN0, 91%). The authors demonstrated that adjuvant chemotherapy significantly improved disease-free survival (hazard ratio 0.49, 95% confidence interval 0.31 to 0.76) as well as metastasis-free survival (hazard ratio 0.49, 95% confidence interval 0.30 to 0.79). However, overall survival data were not yet mature at the time of presentation, so despite the separation of the curves, a meaningful benefit cannot be shown yet. Grade 3 or greater toxicity was experienced by 60% of patients receiving adjuvant chemotherapy and 24% of patients undergoing surveillance.

Previous analyses have demonstrated that patients are much less likely to derive benefit from non-cisplatin based regimes10. Thus, a significant decline in renal function attributable to nephroureterectomy may result in many patients being unable to receive optimal systemic therapy.

Immunotherapy

The data discussed this far center on the use of cytotoxic chemotherapy, whether gemcitabine and cisplatin, MVAC, or gemcitabine and carboplatin, as these have been the traditional agents used for patients with urothelial carcinoma. Following data supporting the role of immunotherapy using checkpoint inhibitors in patients with advanced metastatic urothelial carcinoma, the recently published Phase II PURE-01 trial examined neoadjuvant pembrolizumab for muscle-invasive urothelial bladder carcinoma11. This analysis demonstrated higher rates of pathologic complete response (42%) and downstaging to non-muscle invasive disease (54%) than would be expected from historical use of cytotoxic chemotherapy, though a randomized control was not employed in this analysis. Analyses of durvalumab plus tremelimumab and of gemcitabine plus cisplatin plus pembrolizumab demonstrated similarly promising results. This approach has not, to our knowledge, been tested in upper tract urothelial carcinoma but such an approach may be particularly valuable in these patients.

Conclusions

At the 2018 Society of Urologic Oncology meeting, Dr. Jean Hoffman-Censits presented on the role of neoadjuvant chemotherapy in these patients. She discussed differences between urothelial carcinomas of the bladder and of the upper urinary tract. Notably, she highlighted that pathologic response rates appear to be lower in patients with upper tract urothelial carcinoma (9-15%) as compared to bladder cancer (>20%). The ongoing URANUS trial will better delineate the role of neoadjuvant therapy in upper tract urothelial carcinoma.

Published Date: December 2019
Written by: Zachary Klaassen, MD, MSc
References: 1. Leow JJ, Chong KT, Chang SL, et al. Upper tract urothelial carcinoma: a different disease entity in terms of management. ESMO Open 2016; 1(6):e000126.
2. Catto JW, Azzouzi AR, Amira N, et al. Distinct patterns of microsatellite instability are seen in tumours of the urinary tract. Oncogene 2003; 22(54):8699-706.
3. Kunze E, Wendt M, Schlott T. Promoter hypermethylation of the 14-3-3 sigma, SYK and CAGE-1 genes is related to the various phenotypes of urinary bladder carcinomas and associated with progression of transitional cell carcinomas. Int J Mol Med 2006; 18(4):547-57.
4. Margulis V, Shariat SF, Matin SF, et al. Outcomes of radical nephroureterectomy: a series from the Upper Tract Urothelial Carcinoma Collaboration. Cancer 2009; 115(6):1224-33.
5. Advanced Bladder Cancer Meta-analysis C. Neoadjuvant chemotherapy in invasive bladder cancer: update of a systematic review and meta-analysis of individual patient data advanced bladder cancer (ABC) meta-analysis collaboration. Eur Urol 2005; 48(2):202-5; discussion 205-6.
6. Matin SF, Margulis V, Kamat A, et al. Incidence of downstaging and complete remission after neoadjuvant chemotherapy for high-risk upper tract transitional cell carcinoma. Cancer 2010; 116(13):3127-34.
7. Porten S, Siefker-Radtke AO, Xiao L, et al. Neoadjuvant chemotherapy improves survival of patients with upper tract urothelial carcinoma. Cancer 2014; 120(12):1794-9.
8. Kubota Y, Hatakeyama S, Tanaka T, et al. Oncological outcomes of neoadjuvant chemotherapy in patients with locally advanced upper tract urothelial carcinoma: a multicenter study. Oncotarget 2017; 8(60):101500-101508.
9. Liao RS, Gupta M, Schwen ZR, et al. Comparison of Pathological Stage in Patients Treated with and without Neoadjuvant Chemotherapy for High Risk Upper Tract Urothelial Carcinoma. J Urol 2018; 200(1):68-73.
10. Leow JJ, Martin-Doyle W, Fay AP, et al. A systematic review and meta-analysis of adjuvant and neoadjuvant chemotherapy for upper tract urothelial carcinoma. Eur Urol 2014; 66(3):529-41.
11. Necchi A, Anichini A, Raggi D, et al. Pembrolizumab as Neoadjuvant Therapy Before Radical Cystectomy in Patients With Muscle-Invasive Urothelial Bladder Carcinoma (PURE-01): An Open-Label, Single-Arm, Phase II Study. J Clin Oncol 2018:JCO1801148.

Intra-Luminal Therapy for Patients with Low-Grade Upper Tract Urothelial Carcinoma

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

 
 



Written by: Christopher J.D. Wallis, MD, PhD and Zachary Klaassen, MD, MSc
References:

1. Siegel, Rebecca L., Kimberly D. Miller, and Ahmedin Jemal. "Cancer statistics, 2019." CA: a cancer journal for clinicians 69, no. 1 (2019): 7-34.
2. Rouprêt, Morgan, Marko Babjuk, Eva Compérat, Richard Zigeuner, Richard J. Sylvester, Maximilian Burger, Nigel C. Cowan et al. "European association of urology guidelines on upper urinary tract urothelial carcinoma: 2017 update." European urology 73, no. 1 (2018): 111-122.
3. Petros, Firas G., Roger Li, and Surena F. Matin. "Endoscopic approaches to upper tract urothelial carcinoma." Urologic Clinics 45, no. 2 (2018): 267-286.
4. Samson, Patrick, Arthur D. Smith, David Hoenig, and Zeph Okeke. "Endoscopic Management of Upper Urinary Tract Urothelial Carcinoma." Journal of endourology 32, no. S1 (2018): S-10.
5. Cutress, Mark L., Grant D. Stewart, Paimaun Zakikhani, Simon Phipps, Ben G. Thomas, and David A. Tolley. "Ureteroscopic and percutaneous management of upper tract urothelial carcinoma (UTUC): systematic review." BJU international 110, no. 5 (2012): 614-628.
6. Babjuk, Marko, Maximilian Burger, Eva M. Compérat, Paolo Gontero, A. Hugh Mostafid, Joan Palou, Bas WG van Rhijn et al. "European Association of Urology guidelines on non-muscle-invasive bladder cancer (TaT1 and carcinoma In Situ)-2019 update." European urology (2019).
7. Nepple, Kenneth G., Fadi N. Joudi, and Michael A. O'Donnell. "Review of topical treatment of upper tract urothelial carcinoma." Advances in urology 2009 (2009).
8. Rastinehad, Ardeshir R., and Arthur D. Smith. "Bacillus Calmette-Guerin for upper tract urothelial cancer: is there a role?." Journal of endourology 23, no. 4 (2009): 563-568.
9. de Bruijn, Ernst A., Harm P. Sleeboom, Peter JRO van Helsdingen, Allan T. van Oosterom, Ubbo R. Tjaden, and Robert AA Maes. "Pharmacodynamics and pharmacokinetics of intravesical mitomycin C upon different dwelling times." International journal of cancer 51, no. 3 (1992): 359-364.
10. Donin, Nicholas M., Sandra Duarte, Andrew T. Lenis, Randy Caliliw, Cristobal Torres, Anthony Smithson, Dalit Strauss-Ayali et al. "Sustained-release formulation of mitomycin C to the upper urinary tract using a thermosensitive polymer: a preclinical study." Urology 99 (2017): 270-277.
11. Donin, Nicholas M., Dalit Strauss-Ayali, Yael Agmon-Gerstein, Nadav Malchi, Andrew T. Lenis, Stuart Holden, Allan J. Pantuck, Arie S. Belldegrun, and Karim Chamie. "Serial retrograde instillations of sustained release formulation of mitomycin C to the upper urinary tract of the Yorkshire swine using a thermosensitive polymer: safety and feasibility." In Urologic Oncology: Seminars and Original Investigations, vol. 35, no. 5, pp. 272-278. Elsevier, 2017.
12. Knoedler, John J., and Jay D. Raman. "Intracavitary therapies for upper tract urothelial carcinoma." Expert review of clinical pharmacology 11, no. 5 (2018): 487-493.

Endoscopic Approaches and Emerging Novel Treatments for Upper Tract Urothelial Carcinoma

Upper tract urothelial carcinoma, comprising either the renal pelvis or ureter, is rarer than urothelial carcinoma of the bladder accounting for only 5-10% of all urothelial carcinomas1 (epidemiology of upper tract urothelial cancer, Wallis CJD). However, similar to bladder urothelial carcinoma, not all upper tract urothelial cancer is high-risk and/or patients may not be fit for radical surgery. Although a radical nephroureterectomy is the gold standard treatment for upper tract urothelial cancer, there has been an impetus for developing and assessing less aggressive, less invasive treatment modalities2-4. As such, this article will discuss endoscopic (ureteroscopic and percutaneous), kidney-sparing treatment modalities for upper tract urothelial cancer, as well as focus on several emerging treatments.

Indications for Kidney Sparing/Endoscopic Management

  • Imperative – patients with contraindications for radical surgery: (i) a solitary functioning kidney, (ii) bilateral upper tract urothelial cancer, (iii) baseline renal insufficiency, (iv) poor candidacy for hemodialysis or renal transplantation, (v) significant comorbidities
  • Elective – patients with low-risk non-muscle invasive upper tract urothelial cancer. May be eligible for a partial nephrectomy, segmental ureterectomy, or endoscopic management
The 2017 European Association of Urology Guidelines on upper tract urothelial cancer5 suggest that ureteroscopic endoscopic ablation can be considered in patients with clinically low-risk cancer in addition to the following situations: (i) a laser generator and equipment is available for biopsies, (ii) when a flexible rather than rigid ureteroscope is available, (iii) the patient is informed of the need for earlier or closer surveillance, and (iv) complete tumor resection is achievable. Furthermore, the Guidelines suggest that percutaneous ablation can be considered for low-risk upper tract urothelial cancer in the renal pelvis, particularly for tumors in the lower calyceal system that are inaccessible or difficult to manage by flexible ureteroscopy.

Ureteroscopic Management

Endoscopic evaluation, typically by ureteroscopy, is crucial for the initial diagnosis, risk stratification, and subsequent treatment planning for patients with upper tract urothelial cancer. Information from endoscopy helps assess tumor location, multifocality, architecture and allows the clinician to obtain a tissue diagnosis. However, ureteroscopic biopsies can be technically challenging given the limited ureteroscopic biopsy instruments that can traverse the small working channel. Some experts have advocated that the visual characteristics of the tumor may be able to predict disease aggressiveness, such as sessile-appearing tumors being more likely to be higher grade/stage .6 Several techniques for achieving a tissue diagnosis have been described, including multiple urine and washing samples and multiple quality biopsies to ensure sufficient tissue for pathological assessment; the most commonly used biopsy tools include the Piranha forceps (Boston Scientific, Marlborough, MA) and the BIGopsy forceps (Cook Medical, Bloomington, IN).2 For larger, papillary tumors, a stone basket (ie. nitinol) can be used for snaring and debulking the tumor.  

One of the benefits of a ureteroscopic approach is that a single procedure can be both diagnostic and therapeutic. When possible, use of a ureteral access sheath is ideal in that it allows atraumatic multiple insertions of the ureteroscope, especially important when encountered with a large tumor volume7. Following multiple biopsies for tissue diagnosis, a laser can be used both for additional tumor resection and fulguration (for hemostasis) of the tumor bed. The most commonly used lasers are the holmium:yttrium-aluminum-garnet (YAG) laser and the neodymium-doped (Nd):YAG laser. The holmium laser is typically better suited for smaller tumors, however, it requires contact with the tissue in order to be effective. The Nd: YAG laser has a smaller wavelength, is able to penetrate deeper (5-6 mm), and does not require direct tissue contact. Although less readily available, electrocautery resection is also possible with a 10-13Fr rigid ureteral resectoscope (Karl Storz Endoscopy, Tuttlingen, Germany); this scope allows resection of tumors similar to a loop used for transurethral resection of bladder tumors2.

Currently, there is no Level I evidence assessing oncologic outcomes of patients undergoing ureteroscopic management of upper tract urothelial cancer. Retrospective series to date are all limited to fewer than 100 patients. The largest retrospective series with more than two years of follow-up was published by Grasso and colleagues (n=82)8 noting 81% recurrence rate in the upper tract, 57% in the bladder, 19% of patients progressing to surgical resection, and a 74% and 87% overall and cancer-specific survival rate, respectively. Petros et al summarized these retrospective studies with the following outcomes:2

  • Median follow-up: 24-58 months
  • Upper tract recurrence rate: 65%
  • Bladder recurrence rate: 44%
  • Progression to surgical resection rate: 0-33%
  • Overall survival rate: 35-100%
  • Cancer-specific survival rate: 70-100%
In general, ureteroscopic management of upper tract urothelial cancer is associated with high risk of recurrence and a not insignificant rate of progression to more radical surgery.

Percutaneous Management

Antegrade percutaneous endoscopic treatment of upper tract urothelial carcinoma is typically reserved for patients with low-grade, large volume tumors that are either anatomically or technically challenging for ureteroscopic management, ie. lower pole tumors. This approach is particularly advantageous for patients that have had a prior cystectomy and urinary diversion. A major benefit of percutaneous management is the ability to use larger instruments that are able to fit through a nephroscope, including loop cautery for debulking large tumors. All of the laser biopsy instruments listed above for ureteroscopic management are also feasible for the percutaneous approach. The primary risk of percutaneous management of upper tract urothelial carcinoma (aside from those traditionally associated with percutaneous management of nephrolithiasis) is disruption of the urothelium, which may lead to a theoretically increased risk of tumor seeding into the retroperitoneum.2

Similar to ureteroscopic management of upper tract urothelial carcinoma, oncologic outcomes have relied on retrospective studies of fewer than 100 patients. However, one study by Motamedinia et al.9 identified 141 patients who underwent percutaneous resection with a median follow-up of 66 months. They noted that recurrence occurred in 37% of low-grade patients and 63% of high-grade patients, with a median time to recurrence of 71.4 vs 36.4 months, respectively. On multivariable analysis, grade was the only predictor of recurrence (HR 2.12, p = 0.018) and radical nephroureterectomy was avoided in 87% of patients. Petros and colleagues2 summarized oncologic outcomes of percutaneous management among studies with a minimum 2-year follow-up (n=361):

  • Median follow-up: 24-66 months
  • Upper tract recurrence rate: 40%
  • Bladder recurrence rate: 24%
  • Progression to surgical resection rate: 6-50%
  • Overall survival rate: 40-90%
  • Cancer-specific survival rate: 75-100%

Emerging Novel Treatments

Several new and exciting treatments are under development with regards to minimally invasive treatment of upper tract urothelial cancer. As highlighted above, the recurrence rate for endoscopic management is high (40-65% on pooled analysis)2 and these approaches are not well suited to treatment of multifocal disease or carcinoma in situ. Thus, much research has been directed for improving the deliverability of topical agents to the upper tracts. One of the challenges is difficulty concentrating therapeutic levels of these agents in the upper tract for more than a brief period of time secondary to ureteral peristalsis rapidly draining topical treatment from the pelvis and ureter. Specifically, mitomycin C exposure time to the urothelium is critical for efficacy.10 RTGel™ is a reverse-thermal hydrogel composed of a combination of polymers that allows it to exist as a liquid at cold temperatures but solidifies to a gel state at body temperature.11 This product was developed to address the constraints of the upper urinary tract, where continuous urine production and ureteral peristalsis prevents drug retention in the upper tract. Subsequently, MitoGel Ôwas developed as a novel formulation of RTGel combined with mitomycin C. The hypothesis for MitoGel is that upon delivery to the upper urinary tract, MitoGel 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. Using a preclinical swine animal model (n=23), Donin et al,11 noted that after antegrade instillation of MitoGel, the product remained visible in the pelvicalyceal system on fluoroscopic and computed tomography imaging for 4-6 hours after instillation. Furthermore, on necropsy, they noted that mitomycin C plasma levels were well within acceptable safety thresholds and that there was no evidence of urinary obstruction, acute kidney injury, sepsis, or myelosuppression. Donin and colleagues subsequently confirmed these safety results in a study assessing six once-weekly unilateral retrograde instillations of Mitogel.12

The OLYMPUS study (NCT02793128) is a prospective single-arm ongoing clinical trial designed to assess the efficacy, safety, and tolerability of MitoGel in patients with low grade, noninvasive upper tract urothelial cancer. Eligible patients are treated with MitoGel once weekly for a total of six times in a retrograde fashion; patients demonstrating a complete response are treated with MitoGel once monthly for a total of 11 instillations as maintenance, or until the first recurrence. The primary outcomes are complete response rate defined as the percent of patients with complete response at the primary disease evaluation visit (~11 weeks), and adverse event rates (over ~2 years). Secondary outcomes include:

(i) Long-term durability of complete response (12 months)
(ii) Complete response rates at 3, 6, and 9 months
(iii) Partial response to treatment (~11 weeks)
(iv) Mitomycin C level in blood plasma

The target recruitment goal is 71 patients with an estimated study completion date of February 2020.

Previous studies assessing differential gene expression between upper tract and bladder urothelial carcinoma using microarray data suggest that upper tract tumors tend to have high expression of genes associated with a luminal subtype.13 Furthermore, one particular gene highly expressed in upper tract tumors is SLITRK6, an integral membrane protein known to have high levels of expression in certain carcinomas, but low levels in the majority of other tissues.14 An antibody to SLITRK6 protein has been developed and linked to a cytotoxic agent called monomethyl auristatin E (AGS15E), a microtubule-disrupting agent.15, 16 ASG-15C was chosen among seven anti-SLITRK6 antibodies and monomethyl auristatin E was chosen due to its efficacy in tumor inhibition and regression. Upon binding to SLITRK6, ASG-15ME is rapidly internalized and trafficked to lysosomes and early endosomes. An ongoing Phase I dose escalation trial of AGS15E in patients with metastatic urothelial carcinoma presented initial interim trial results at the ESMO 2016.17 This trial includes patients previously treated with ≥ 1 prior chemotherapy regimens; SLITRK6 expression was determined by immunohistochemistry. Disease assessments were performed every 8 weeks using RECIST v 1.1 criteria and ASG-15ME was administered IV weekly for 3 out of every 4 weeks until no further benefit. Six dose levels were assessed: 0.1, 0.25, 0.5, 0.75, 1, and 1.25 mg/kg. At the time of analysis, 51 pts were enrolled and 93% were SLITRK6 positive. Of 42 evaluable patients at doses considered active (doses ≥0.5 mg/kg), one had a complete response and 13 had a partial response (ORR =33%). Adverse event rate was high (91%) and the most common treatment-related adverse event was fatigue (44%). Serum concentrations of ASG-15ME decreased multi-exponentially and half-life was 3.1 days. In heavily pre-treated individuals, novel antibody-drug conjugates continue to be explored for therapeutic benefit.

Conclusions  

Endoscopic management of upper tract urothelial cancer is technically feasible but associated with high rates of recurrence and non-insignificant rates of progression necessitating radical surgical treatment. Endoscopic management should be reserved for low-grade tumors and patients that have contraindications to radical nephroureterectomy. Research is ongoing, particularly for improving delivery of topical agents to decrease recurrence rates.

Published Date: April 15th, 2019
Written by: Zachary Klaassen, MD, MSc
References:
  1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69:7-34.
  2. Petros FG, Li R, Matin SF. Endoscopic Approaches to Upper Tract Urothelial Carcinoma. Urol Clin North Am. 2018;45:267-86.
  3. Samson P, Smith AD, Hoenig D, Okeke Z. Endoscopic Management of Upper Urinary Tract Urothelial Carcinoma. J Endourol. 2018;32:S10-S6.
  4. Cutress ML, Stewart GD, Zakikhani P, Phipps S, Thomas BG, Tolley DA. Ureteroscopic and percutaneous management of upper tract urothelial carcinoma (UTUC): systematic review. BJU Int. 2012;110:614-28.
  5. Roupret M, Babjuk M, Comperat E, Zigeuner R, Sylvester RJ, Burger M, et al. European Association of Urology Guidelines on Upper Urinary Tract Urothelial Carcinoma: 2017 Update. Eur Urol. 2018;73:111-22.
  6. Williams SK, Denton KJ, Minervini A, Oxley J, Khastigir J, Timoney AG, et al. Correlation of upper-tract cytology, retrograde pyelography, ureteroscopic appearance, and ureteroscopic biopsy with histologic examination of upper-tract transitional cell carcinoma. J Endourol. 2008;22:71-6.
  7. Raman JD, Park R. Endoscopic management of upper-tract urothelial carcinoma. Expert Rev Anticancer Ther. 2017;17:545-54.
  8. Grasso M, Fishman AI, Cohen J, Alexander B. Ureteroscopic and extirpative treatment of upper urinary tract urothelial carcinoma: a 15-year comprehensive review of 160 consecutive patients. BJU Int. 2012;110:1618-26.
  9. Motamedinia P, Keheila M, Leavitt DA, Rastinehad AR, Okeke Z, Smith AD. The Expanded Use of Percutaneous Resection for Upper Tract Urothelial Carcinoma: A 30-Year Comprehensive Experience. J Endourol. 2016;30:262-7.
  10. De Bruijn EA, Sleeboom HP, van Helsdingen PJ, van Oosterom AT, Tjaden UR, Maes RA. Pharmacodynamics and pharmacokinetics of intravesical mitomycin C upon different dwelling times. Int J Cancer. 1992;51:359-64.
  11. Donin NM, Duarte S, Lenis AT, Caliliw R, Torres C, Smithson A, et al. Sustained-release Formulation of Mitomycin C to the Upper Urinary Tract Using a Thermosensitive Polymer: A Preclinical Study. Urology. 2017;99:270-7.
  12. Donin NM, Strauss-Ayali D, Agmon-Gerstein Y, Malchi N, Lenis AT, Holden S, et al. Serial retrograde instillations of sustained release formulation of mitomycin C to the upper urinary tract of the Yorkshire swine using a thermosensitive polymer: Safety and feasibility. Urol Oncol. 2017;35:272-8.
  13. Sanford T, Porten S, Meng MV. Molecular Analysis of Upper Tract and Bladder Urothelial Carcinoma: Results from a Microarray Comparison. PLoS One. 2015;10:e0137141.
  14. Aruga J, Yokota N, Mikoshiba K. Human SLITRK family genes: genomic organization and expression profiling in normal brain and brain tumor tissue. Gene. 2003;315:87-94.
  15. Vlachostergios PJ, Jakubowski CD, Niaz MJ, Lee A, Thomas C, Hackett AL, et al. Antibody-Drug Conjugates in Bladder Cancer. Bladder Cancer. 2018;4:247-59.
  16. Morrison K, Challita-Eid PM, Raitano A, An Z, Yang P, Abad JD, et al. Development of ASG-15ME, a Novel Antibody-Drug Conjugate Targeting SLITRK6, a New Urothelial Cancer Biomarker. Mol Cancer Ther. 2016;15:1301-10.
  17. Petrylak D, Heath E, Sonpavde G, George S, Morgans AK, Eigl BJ. Interim analysis of phase 1 dose escalation trial of the antibody-drug conjugate (ADC) ASG15E (ASG15ME) in patients (Pts) with metastatic urothelial cancer (mUC). Ann Oncol. 2016;27:266-95.

Delays in the Treatment of Upper Tract Urothelial Carcinoma During the COVID-19 Pandemic

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

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

Written by: Zachary Klaassen, MD, MSc
References: 1. Rouprêt, Morgan, Marko Babjuk, Eva Compérat, Richard Zigeuner, Richard J. Sylvester, Maximilian Burger, Nigel C. Cowan et al. "European association of urology guidelines on upper urinary tract urothelial carcinoma: 2017 update." European urology 73, no. 1 (2018): 111-122.
2. Shariat, Shahrokh F., Ricardo L. Favaretto, Amit Gupta, Hans-Martin Fritsche, Kazumasa Matsumoto, Wassim Kassouf, Thomas J. Walton et al. "Gender differences in radical nephroureterectomy for upper tract urothelial carcinoma." World journal of urology 29, no. 4 (2011): 481-486.
3. Cowan, Nigel C., Ben W. Turney, Nia J. Taylor, Catherine L. McCarthy, and Jeremy P. Crew. "Multidetector computed tomography urography for diagnosing upper urinary tract urothelial tumour." BJU international 99, no. 6 (2007): 1363-1370.
4. COVID, CDC, and Response Team. "Severe outcomes among patients with coronavirus disease 2019 (COVID-19)—United States, February 12–March 16, 2020." MMWR Morb Mortal Wkly Rep 69, no. 12 (2020): 343-346.
5. Grasselli, Giacomo, Alberto Zangrillo, Alberto Zanella, Massimo Antonelli, Luca Cabrini, Antonio Castelli, Danilo Cereda et al. "Baseline characteristics and outcomes of 1591 patients infected with SARS-CoV-2 admitted to ICUs of the Lombardy region, Italy." JAMA (2020).
6. Lee, Jung Keun, Ki Bom Kim, Yong Hyun Park, Jong Jin Oh, Sangchul Lee, Chang Wook Jeong, Seong Jin Jeong, Sung Kyu Hong, Seok-Soo Byun, and Sang Eun Lee. "Correlation between the timing of diagnostic ureteroscopy and intravesical recurrence in upper tract urothelial cancer." Clinical genitourinary cancer 14, no. 1 (2016): e37-e41.
7. Nison, Laurent, Morgan Rouprêt, Grégory Bozzini, Adil Ouzzane, François Audenet, Géraldine Pignot, Alain Ruffion et al. "The oncologic impact of a delay between diagnosis and radical nephroureterectomy due to diagnostic ureteroscopy in upper urinary tract urothelial carcinomas: results from a large collaborative database." World journal of urology 31, no. 1 (2013): 69-76.
8. Waldert, Matthias, Pierre I. Karakiewicz, Jay D. Raman, Mesut Remzi, Hendrik Isbarn, Yair Lotan, Umberto Capitanio, Karim Bensalah, Michael J. Marberger, and Shahrokh F. Shariat. "A delay in radical nephroureterectomy can lead to upstaging." BJU international 105, no. 6 (2010): 812-817.
9. Sundi, Debasish, Robert S. Svatek, Vitaly Margulis, Christopher G. Wood, Surena F. Matin, Colin P. Dinney, and Ashish M. Kamat. "Upper tract urothelial carcinoma: impact of time to surgery." In Urologic Oncology: Seminars and Original Investigations, vol. 30, no. 3, pp. 266-272. Elsevier, 2012.
10. Xia, Leilei, Benjamin L. Taylor, Jose E. Pulido, and Thomas J. Guzzo. "Impact of surgical waiting time on survival in patients with upper tract urothelial carcinoma: A national cancer database study." In Urologic Oncology: Seminars and Original Investigations, vol. 36, no. 1, pp. 10-e15. Elsevier, 2018.
11. Birtle, Alison, Mark Johnson, John Chester, Robert Jones, David Dolling, Richard T. Bryan, Christopher Harris et al. "Adjuvant chemotherapy in upper tract urothelial carcinoma (the POUT trial): a phase 3, open-label, randomised controlled trial." The Lancet (2020).
12. Gillessen, Silke, and Thomas Powles. "Advice Regarding Systemic Therapy in Patients with Urological Cancers During the COVID-19 Pandemic." (2020).

Upper Tract Urothelial Carcinoma

Upper tract urothelial carcinoma (UTUC) comprises any malignancies arising from the urothelium between the level of the renal pelvis and the distal ureter. Owing to their relatively rarity, there is generally little data to guide the management of patients with these tumors and much of practice is extrapolated from the management of urothelial cancer of the bladder. A recent genomic assessment of UTUC demonstrates novel mutations and distributions of mutations, compared with bladder cancer.1 Further, anatomic differences between the upper urinary tract and the bladder affect the validity of extrapolating data from one disease site to the other. In the ureter, the muscular layer surrounding the urothelium is marked attenuated compared to the detrusor. Additionally, in the renal pelvis, the urothelium may directly about the renal parenchyma.

Epidemiology

Upper tract disease represents approximately 5-10% of all urothelial malignancies.2 There is significant geographic variation in the incidence of these cancers, likely due to differences in the prevalence of underlying risk factors. In Balkan nations, UTUC may represent up to 40% of all kidney-related cancers. In Western nations, the incidence is approximately 2 per 100,000 population.3 As with bladder cancer, the incidence of these cancers peaks in individuals in their 8th and 9th decades of life.

Interestingly, the incidence of UTUC appears to be increasing. Accompanying this has been a change in tumor stage, with an increasing proportion of earlier stage neoplasms.4

While bladder common is nearly 4 times as common in men as in women, the differential is closer to 2:1 for UTUC. Data is mixed on the association between patient gender and outcomes in UTUC. While some authors have reported that women are more likely to have advanced stage of disease5, other have not demonstrated this.6 Similarly, some groups report worse outcomes among women5 following nephroureterectomy, while other analyses have demonstrated no difference.6

Utilizing a large, multi-institutional cohort, Raman et al. examined predictors of recurrence and cancer-specific mortality among patients undergoing radical nephroureterectomy.7 They found that pathological tumor stage, nodal involvement, and tumor grade were associated with survival. Tumor location, whether in the renal pelvis or ureter, was not significantly associated with oncologic outcomes.

Etiology

Most, though not all, risk factors for the develop of UTUC are similar to the development of bladder cancer. Particular focus here is made of the unique risk factors including hereditary syndromes and uncommon environmental exposures.

Genetic and environmental risk factors may contribute to the development of UTUC. Hereditary UTUC is associated with hereditary nonpolyposis colorectal carcinoma (HNPCC) syndrome, or Lynch syndrome.8 These patients may also have an increased risk of bladder cancers8, though whether this is from a urothelial field defect or seeding from the upper tract is unclear. HNPCC should be suspected among younger patients or those with a personal or family (two first-degree relatives) history of HNPCC-associated cancers, including colon or endometrial cancers.

A number of environmental risk factors are known for UTUC. First among these is aristolochic acid nephropathy. This is felt to be the common pathway between both Balkan endemic nephropathy and Chinese herb nephropathy (associated with consumption of Aristolochia fangchi) and UTUC.9 In Western countries, smoking is a much more common risk factor. This is associated with the production of N-hydroxylamine from aromatic amines. For reasons that are poorly understood, smoking seems to confer a higher risk of ureteral tumors than renal pelvic lesions.10 Previous reports suggested that coffee consumption may also be associated with UTUC but further work has suggested that these results likely represent Berkson's bias, due to the relationship between smoking and coffee consumption. Analgesic abuse, particularly of phenacetin, has also been well documented to be associated with the development of UTUC. However, the frequency of this exposure is rapidly declining and, as such, associated cases are relatively rare today. Arsenic exposure, typically through contaminated water, has also demonstrated an association with the development of UTUC. Interestingly, arsenic-associated UTUC demonstrates a female preponderance, unlike the general epidemiologic trends. As with bladder cancer, occupational exposures to aromatic hydrocarbons have been associated with a significantly increased risk of UTUC. Alkylating chemotherapy and chemic laxatives also appear to be associated with increased rates of UTUC. Finally, chronic inflammation may predispose to non-urothelial (squamous cell cancer or adenocarcinoma) of the upper urinary tract.

Association Between UTUC and Bladder Cancer

Significant focus has been directed to the relationship between UTUC and urothelial bladder cancer as a result of their shared tissue of origin. UTUC may occur in approximately 2 to 4% of patients with bladder cancer. However, there is wide variability in this quoted risk owing to differences in bladder cancer pathology and duration of follow-up. UTUC recurrence following bladder cancer treatment is reportedly more common among patients with carcinoma in situ (CIS) of the bladder11 and among those with more advanced (T1 vs Ta) disease.12

Among patients with UTUC, recurrence in the bladder is relatively common. Depending on the report, estimates range from 15 to 75% at 5 years. Thus, routine cystoscopic surveillance is recommended following treatment for UTUC.

Histologic Considerations

The vast majority of upper tract tumors are urothelial in origin (>90%). As with bladder cancer, this may present as CIS, as papillary or sessile lesions, and as solitary lesions or in a multifocal pattern. Histological variants, now relatively well recognized in bladder cancer, may also be found in UTUC. Squamous cell cancers and adenocarcinomas make up a small proportion of upper tract malignancies. Other lesions including benign fibroepithelial polyps and neurofibromas as well as neuroendocrine tumors, hematopoietic tumors, and sarcomas have been reported.

Two benign lesions, papillomas and inverted papillomas, have been associated with synchronous and metachronous development of UTUC. Thus, surveillance is recommended for patients with these lesions.

Clinical Assessment and Evaluation

The majority of patients with UTUC present with gross or microscopic hematuria. In fact, depending on estimates, up to 98% of all patients with UTUC will have hematuria. However, UTUC remains uncommon among patients presenting with hematuria.  Flank pain may also occur and is typically felt to be due to obstruction of the collecting system. UTUC may also present entirely without symptoms as an incidental finding.

Today, triphasic computed tomography (so called CT urography (CTU)) is the imaging modality of choice for the diagnosis of upper tract lesions. The sensitivity of CTU, as well as the negative predictive value, is reported to near 100%.13 Most upper tract lesions present with a filling defect. To distinguish from other causes of such a defect, UTUC typically have a density between 10 and 70 hounsfield units, less than radiolucent stones. In equivocal cases, retrography pyelography, selective ureteric washings for cytology, or ureteroscopy may be necessary.

Due to the association between UTUC and bladder cancer, cystoscopy is necessary to rule-out concomitant bladder cancer. Further, in the workup of a patient with hematuria, bladder cancer is a much more common underlying etiology than UTUC.

In addition to visualizing the lesion, ureteroscopy can allow for histologic diagnosis with biopsy or brushings. However, these biopsies are limited in the amount of tissue that may be samples and, as such, tumor grade is more reliable than stage based on these samples. Staging requires integration of imaging studies as tumor grade.

Cytology may be employed in the work-up of UTUC. While cytology is highly specific, it lacks sensitivity.

Staging, as detailed in the chart below, according to the TNM classification, parallels that of bladder cancer.
table 1 upper tract urothelial carcinoma2x
Upper tract tumors disseminate via lymphatic and hematogenous spread as well as direct extension. The most common sites of metastasis are lungs, liver, bones and lymph nodes. Thus, preoperative staging, depending on primary tumor characteristics, comprises thoracic imaging (CXR or CT), abdominal CT, liver function testing, and bone scan. In addition, for patients for whom nephroureterectomy is being considered, assessment of the contralateral renal function is necessary.

Prognostic Factors

Stage is the most important predictor. Unfortunately, it is sometimes difficult to ascertain stage preoperatively. Certainly, nodal involvement is independently associated with worse survival outcomes. Tumor location, whether in the renal pelvis or ureter, has proven controversial with regards to prognosis. While some studies have suggested no difference14, others have found improved survival among patients with renal pelvic tumors.15 Likely through its association with tumor stage, the presence of hydronephrosis has been shown to be associated with worse survival.16 Larger tumors (typically defined as greater than 3 or 4 cm) are also associated with worse outcomes. Other factors including tumor multifocality, tumor necrosis, and lymphovascular invasion have also been associated with worse outcomes though the data is somewhat contradictory.

A number of molecular markers have been evaluated for prognostication in patients with UTUC. These include cytogentic abnormalities, oncogenes (c-MET and RON), as well as markers of apoptosis (Bcl-2 and surviving), markers of cell migration and invasion (E-cadherin and MMPs), cell cycle progression (p53 and CDKN1B), angiogenesis (HIF-1α), cell proliferation (Ki-67, EGFR, and NF-κB), cell differentiation (uroplakin III and snail), mitosis (aurora-A), and microsatellite instability.

Treatment

The relative rarity of UTUC has precluded many large trials to guide treatment for these patients. As an overarching principle, the least invasive treatment necessary for safe oncologic control of the tumor should be preferred. Depending on tumor characteristics, this may include radical nephroureterectomy (whether open or laparoscopic), segmental ureterectomy, and endoscopic/percutaneous tumor ablations.

Radical nephroureterectomy remains the gold standard for large, high-grade and suspected invasive tumors of the renal pelvis and proximal ureter. A variety of techniques exist for management of the distal ureter though formal excision of a bladder cuff is the gold standard approach.

For patients with low-grade, non-invasive tumors, retrograde endoscopic or percutaneous ablation offer the potential for nephron-sparing treatment.

Perhaps the most notable advance in the treatment of patients with UTUC comes with the recent publication of the POUT trial which assessed the role of adjuvant chemotherapy following nephroureterectomy. Among 248 patients with pT2-4 N0-3 UTUC, Birtle and colleagues randomized patients to 4 cycles of adjuvant gemcitabine-cisplatin or surveillance. They demonstrated a significant improvement in disease-free survival and progression-free survival.

The multifocal and recurrence nature of urothelial carcinoma makes ongoing follow-up critical following any treatment. For patients opting for endoscopic approaches, repeated surveillance ureteroscopy is required. For other patients, cystoscopy, urine cytology and upper tract imaging are required. For patients at increased risk of metastases, thoracic imaging, biochemical studies including liver function testing, and bone scan may be indicated.

Published Date: January 28th, 2019
References:
  1. Moss TJ, Qi Y, Xi L, et al. Comprehensive Genomic Characterization of Upper Tract Urothelial Carcinoma. European urology 2017;72:641-9.
  2. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA: a cancer journal for clinicians 2018;68:7-30.
  3. Roupret M, Zigeuner R, Palou J, et al. European guidelines for the diagnosis and management of upper urinary tract urothelial cell carcinomas: 2011 update. European urology 2011;59:584-94.
  4. David KA, Mallin K, Milowsky MI, Ritchey J, Carroll PR, Nanus DM. Surveillance of urothelial carcinoma: stage and grade migration, 1993-2005 and survival trends, 1993-2000. Cancer 2009;115:1435-47.
  5. Mohamad Al-Ali B, Madersbacher S, Zielonke N, Schauer I, Waldhoer T, Haidinger G. Impact of gender on tumor stage and survival of upper urinary tract urothelial cancer : A population-based study. Wien Klin Wochenschr 2017;129:385-90.
  6. Shariat SF, Favaretto RL, Gupta A, et al. Gender differences in radical nephroureterectomy for upper tract urothelial carcinoma. World journal of urology 2011;29:481-6.
  7. Raman JD, Ng CK, Scherr DS, et al. Impact of tumor location on prognosis for patients with upper tract urothelial carcinoma managed by radical nephroureterectomy. European urology 2010;57:1072-9.
  8. Skeldon SC, Semotiuk K, Aronson M, et al. Patients with Lynch syndrome mismatch repair gene mutations are at higher risk for not only upper tract urothelial cancer but also bladder cancer. European urology 2013;63:379-85.
  9. Grollman AP, Shibutani S, Moriya M, et al. Aristolochic acid and the etiology of endemic (Balkan) nephropathy. Proceedings of the National Academy of Sciences of the United States of America 2007;104:12129-34.
  10. McLaughlin JK, Silverman DT, Hsing AW, et al. Cigarette smoking and cancers of the renal pelvis and ureter. Cancer research 1992;52:254-7.
  11. Slaton JW, Swanson DA, Grossman HB, Dinney CP. A stage specific approach to tumor surveillance after radical cystectomy for transitional cell carcinoma of the bladder. The Journal of urology 1999;162:710-4.
  12. Wright JL, Hotaling J, Porter MP. Predictors of upper tract urothelial cell carcinoma after primary bladder cancer: a population based analysis. The Journal of urology 2009;181:1035-9; discussion 9.
  13. Caoili EM, Cohan RH, Korobkin M, et al. Urinary tract abnormalities: initial experience with multi-detector row CT urography. Radiology 2002;222:353-60.
  14. Isbarn H, Jeldres C, Shariat SF, et al. Location of the primary tumor is not an independent predictor of cancer specific mortality in patients with upper urinary tract urothelial carcinoma. The Journal of urology 2009;182:2177-81.
  15. Ouzzane A, Colin P, Xylinas E, et al. Ureteral and multifocal tumours have worse prognosis than renal pelvic tumours in urothelial carcinoma of the upper urinary tract treated by nephroureterectomy. European urology 2011;60:1258-65.
  16. Ng CK, Shariat SF, Lucas SM, et al. Does the presence of hydronephrosis on preoperative axial CT imaging predict worse outcomes for patients undergoing nephroureterectomy for upper-tract urothelial carcinoma? Urologic oncology 2011;29:27-32

Nephron-Sparing Approaches in Upper Tract Urothelial Carcinoma

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.

Written by: Zachary Klaassen, MD, MSc
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13. de Bruijn, Ernst A., Harm P. Sleeboom, Peter JRO van Helsdingen, Allan T. van Oosterom, Ubbo R. Tjaden, and Robert AA Maes. "Pharmacodynamics and pharmacokinetics of intravesical mitomycin C upon different dwelling times." International journal of cancer 51, no. 3 (1992): 359-364.
14. Donin, Nicholas M., Dalit Strauss-Ayali, Yael Agmon-Gerstein, Nadav Malchi, Andrew T. Lenis, Stuart Holden, Allan J. Pantuck, Arie S. Belldegrun, and Karim Chamie. "Serial retrograde instillations of sustained release formulation of mitomycin C to the upper urinary tract of the Yorkshire swine using a thermosensitive polymer: safety and feasibility." In Urologic Oncology: Seminars and Original Investigations, vol. 35, no. 5, pp. 272-278. Elsevier, 2017.