Upper Tract Urothelial Carcinoma COE Articles

Articles

  • ASCO GU 2018: Results of POUT: A Phase III Randomized Trial of Perioperative Chemotherapy versus Surveillance in Upper Tract Urothelial Carcinoma (UTUC)

    San Francisco, CA (UroToday.com) The management of patients with upper tract urothelial carcinoma (UTUC) is challenging due to the lack of high-level evidence, which results from the disease’s overall rarity. The standard of care for patients with high-grade disease or those suspected to have invasive disease is a radical nephroureterectomy, with some advocating for the added use neoadjuvant or adjuvant platinum-based chemotherapy. The added benefit of platinum chemotherapy in patients with locally invasive UTUC has been extrapolated from the bladder cancer literature and supported by several retrospective and population reports. Dr. Alison J. Birtle presents results of the first randomized clinical trial in the field for patients with UTUC.  A Phase III Randomised Trial of Peri-Operative Chemotherapy Versus sUrveillance in Upper Tract Urothelial Cancer (POUT) trial which assessed the added benefit of using platinum-based chemotherapy in the adjuvant setting in patients undergoing a radical nephroureterectomy. 
    Published February 9, 2018
  • AUA 2018: Results from Interim Analysis of Pivotal Phase 3 Trial of UGN-101 for Non-Surgical Treatment of Upper Tract Urothelial Cancer

    San Francisco, CA (UroToday.com) -- UroGen Pharma Ltd., a clinical-stage biopharmaceutical company developing treatments to address unmet needs in the field of urology, with a focus on uro-oncology,  announced a new data presentation from an interim analysis of the ongoing pivotal Phase 3 OLYMPUS clinical trial of UGN-101 (MitoGel™), an investigational mitomycin formulation for the non-surgical treatment of low-grade upper tract urothelial cancer (UTUC). The full interim analysis will be presented on Monday, May 21, 2018 in an oral presentation during the plenary session at the 113th American Urological Association's (AUA) Annual Meeting in San Francisco.
    Published April 10, 2018
  • AUA 2019: Nephron-sparing Management of Low Grade UTUC with UGN-101 for Instillation: The Olympus Trial Experience

    Chicago, IL (UroToday.com) Low grade upper tract urothelial carcinoma (LG UTUC) can be managed with endoscopic resection/ablation however, the associated high recurrence rate requires repetitive intervention and intercavitary therapy for the frequently recurrent and multifocal disease. Many patients have difficulty to access tumors or unresectable tumor volume, requiring radical nephroureterectomy (RNU). Preliminary data from a compassionate use program demonstrated that LG UTUC could be chemically ablated with mitomycin gel (UGN-101).
    Published May 6, 2019
  • BCAN 2019: FDA Collaboration with the Bladder Cancer Community

    Washington, DC (UroToday.com) The expert panel of providers and FDA discussed ongoing and future collaborations with the FDA and bladder cancer. The FDA Oncology Center of Excellence (OCE) leverages the combined skills of regulatory scientists and reviewers. The panel reviewed the structure of the OCE and how expedited programs within the FDA strive to accelerate drug development and approval.

    Chana Weinstock from the FDA presented ongoing engagement between stakeholders as the next generation of clinical trials are designed. The Office of Hematology and Oncology is composed of >80 medical oncologists and a radiation oncologist with expertise in GU malignancies. They review investigational new drugs, new drug applications, and biological license applications. All providers maintain regular patient contact in addition to their FDA responsibilities. There are various stages of drug development which include fast-track, breakthrough therapy, priority review, and accelerated approval. 

    Presented by: Chana Weinstock, MD, Genitourinary Oncology Team Leader, FDA, Silver Spring, MD 

    Written by: Stephen B. Williams, MD, Medical Director for High Value Care; Chief of Urology, Associate Professor, Director of Urologic Oncology, Director Urologic Research, The University of Texas Medical Branch at Galveston, TX and Ashish M. Kamat, MD, Professor, Department of Urology, Division of Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX at the 2019 Bladder  Cancer Advocacy Network  (BCAN) Think Tank August 8-10,  2019  - the Capital Hilton, Washington, DC, USA
    Published August 9, 2019
  • EAU 2019: A Rational Approach to Systemic Treatment of UTUC

    Barcelona, Spain (UroToday.com)  Dr. Sridhar, a medical oncologist from the University of Toronto, provided a summary of the current status of chemotherapy for upper tract urothelial carcinoma (UTUC).

    UTUC accounts for 5-10% of urothelial malignancies, of which 60% are invasive at disease presentation. Radical nephroureterectomy remains the standard of care for localized and invasive disease. The 5-year overall survival for pT2-pT3 disease is <50% and a dismal <10% for pT4 disease. It is important to note that due to a paucity of evidence, the benefit of perioperative chemotherapy is extrapolated from bladder cancer. However, although UTUC histology is similar to bladder cancer, embryonic origin, genomic and epigenomic features, staging and prognosis differ between the two. That being said, urothelial cancers appear to be quite sensitive to chemotherapy. So, in addition to the extrapolation from the bladder cancer world, there is new emerging data and strong rationale for perioperative chemotherapy in UTUC.
    Published March 21, 2019
  • EAU 2019: Neo-Adjuvant versus Adjuvant Chemotherapy in Upper Tract Urothelial Carcinoma: A Feasibility Phase II Randomized Clinical Trial - URANUS

    Barcelona, Spain (UroToday.com) Upper tract urothelial carcinoma (UTUC) is a rare condition, making large clinical trials difficult to accrue for. More importantly, known concerns with the accuracy of pre-operative staging, and therefore, difficulties in accurately identifying high-risk patients make clinical trial accrual and accuracy difficult. As such, much of the data for UTUC is often extrapolated from the bladder cancer urothelial carcinoma literature.
    Published March 17, 2019
  • 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.
    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.
    Published April 15, 2019
  • ESOU 2019: New Perspectives in Upper Tract Urothelial Cancer Treatment

    Prague, Czech Republic (UroToday.com) Dr. Morgan Roupret, a recognized expert in the management of upper tract urothelial carcinoma (UTUC) and the senior author of the EAU guidelines, provided a talk on new perspectives in UTUC treatment. He had four main points that he spent the most time on, which I highlight below.
    Published January 20, 2019
  • Expert Commentary: Circulating Tumor Cells in Bladder and Upper Tract Urothelial Carcinoma

    Circulating tumor cells (CTCs) are cancer cells shed from the tumor that enter the circulation. Isolating circulating tumor cells from urothelial carcinoma patients has several potential diagnostic, prognostic and predictive clinical applications but the available data has been inconclusive.
    Published July 11, 2017
  • Expert Commentary: The Molecular Characteristics of Upper Tract Urothelial Carcinoma

    Upper tract urothelial carcinoma is less common than bladder urothelial carcinoma. The biological characteristics of this form of the disease is not completely understood. A new study published in European Urology by Moss et al. performed an integrated DNA, RNA and protein analysis of upper tract urothelial carcinoma to characterize its molecular landscape. 
    Published July 11, 2017
  • Mismatch Repair Gene Alterations and Microsatellite Instability in Upper Tract Urothelial Carcinoma - Expert Commentary

    Lynch Syndrome (LS) is a common hereditary cancer syndrome that is characterized by mutations in the mismatch repair (MMR) genes. The three most common malignancies in LS patients are colorectal, endometrial and upper tract urothelial carcinoma (UTUC). Unlike colorectal and endometrial carcinoma, universal MMR immunohistochemistry (IHC) and microsatellite instability (MSI) testing are not routinely performed in all the UTUC cases.
    Published September 27, 2018
  • Mutational Analysis Reveals the Relationship Between Upper Tract and Lower Tract Urothelial Carcinomas - Expert Commentary

    Although urothelial carcinomas of the bladder and upper tract urothelial carcinoma (UTUC) can have similar histology, they significantly differ in prevalence and risk factors. A recent paper published by Audenet et al. in Clinical Cancer Research explored the genetic relatedness between UTUC and urothelial carcinomas of the bladder. The cohort included 195 UTUC patients and 454 urothelial carcinomas of the bladder patients with no prior history of UTUC. The investigators analyzed matched tumor and germ-line DNA by using targeted NGS platform (MSK-IMPACT). 
    Published March 7, 2019
  • Survival Benefit of Chemotherapy in Metastatic Upper Tract Urothelial Carcinoma - Expert Commentary

    Upper tract urothelial carcinoma (UTUC) is a distinct clinical entity with poor clinical outcomes. A recent paper published by Nazzani et al. in Clinical Genitourinary Cancer studied the efficacy of chemotherapy in treating non-surgically treated metastatic upper tract urothelial carcinoma (mUTUC) in a large cohort. The investigators identified 539 patients with non-surgically treated mUTUC within the Surveillance, Epidemiology, and End Results database (2004-2014). Of these, 277 (51.4%) received chemotherapy. The investigators compared the overall mortality and cancer-specific mortality in the group that received chemotherapy to the control group. 
    Published March 11, 2019
  • 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 years5.

    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 nephroureterectomy6. 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 carcinoma7. 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 alone8. 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 Hopkins9. 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 downstaging1. 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.
    Written by: Zachary Klaassen, MD, MSc and Christopher J.D. Wallis, MD, PhD
    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.
    Published December 10, 2019
  • 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.
    Written by: Christopher J.D. Wallis, MD, PhD
    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
    Published January 29, 2019