Upper tract urothelial cancer (UTUC) represents approximately 5%-10% of all urothelial cancers, although the incidence is increasing. Modifiable risk factors include exposure to toxins such as tobacco smoke, industrial toxins (including aromatic hydrocarbons, coal, coke, chlorinated solvents, and tars), arsenic, the analgesic phenacetin, and aristolochic acid. Produced by plants of the genus Aristolochia, aristolochic acid can contaminate grain and is found in some traditional Chinese medicine. Non-modifiable risks including gender (2:1 male: female) and genetics (eg, microsatellite instability and Lynch Syndrome).1

Despite improvements in urinary markers, pathology, imaging and endoscopy, the diagnosis and management of UTUC is complex. Unlike with bladder cancer, the diagnosis and management is hindered by: (1) lack of early symptoms, (2) limitations of radiographic diagnostic tests for small luminal tumors, (3) complexities and variations in upper tract anatomy, (4) need for multiple forms of evaluation to confirm the diagnosis, (5) poor predictive value of biopsy to assess grade and stage, (6) need to map the extent of the disease within a single or both kidneys, and (7) absence of comprehensive treatment strategies and guidelines focused on matching treatment to UTUC biology while simultaneously sparing nephrons and preserving renal function. As such, many patients are subjected to repeated laboratory, urine, imaging, and endoscopic evaluations, often under anesthesia. In the case of low-grade UTUC, current treatments options include endoscopic attempts using thermal ablation (eg, laser or cautery) with repetitive surveillance or overtreatment via nephroureterectomy with resultant loss of global kidney function.

While it has been estimated that bladder cancer is among the most expensive tumors to manage on a per-patient basis, due in large part to surgical, imaging, and surveillance intensity,2 UTUC may in fact be costlier given the complexities of ongoing and episodic management expenses, surgical risks, long-term complications of progressive chronic kidney disease (CKD) and/or the need for renal replacement therapy. These factors warrant a renewed look at diagnostic and therapeutic options for low-grade UTUC.

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Guidelines and risk stratification

Algorithms and guidelines for management of UTUC are limited and often bundled with those of bladder cancer due to the lower incidence and prevalence of UTUC, its concurrence in patients with bladder cancer, a lack of recognition of UTUC as a distinct biological entity, and lack of randomized data addressing UTUC, particularly for low-grade, low-stage disease. The American Urological Association, the American Society of Clinical Oncology, and the European Society for Medical Oncology do not offer guidelines managing UTUC. The National Comprehensive Cancer Network (NCCN) relegates their UTUC guidelines to the subtext of those on management of bladder cancer.3 Among major urologic and/or oncologic professional societies, only the European Association of Urology has developed specific UTUC guidelines.4

As with urothelial cancers (UC) of the bladder cancer, UTUC risk is largely based on stage and grade. Unfortunately, unlike with bladder cancer, clinical staging is notoriously poor while endoscopic stage and grade are far more difficult given the limitations of (1) upper-tract radiography, (2) endoscopic visibility and mapping, (3) endoscopic tissue sampling given small luminal size and, (4) adequacy of endoscopic instrumentation limiting resection particularly given the thin-walled upper tract anatomy.

While the AUA has established risk stratification criteria for non-muscle invasive bladder cancer (NMIBC) as low, intermediate and high risk,5 no such system exists for UTUC. Instead, World Health Organization criteria have been adopted. These criteria divide tumors into low and high risk based on tumor size, location, focality, cytology, grade on biopsy, signs of invasion on imaging,6 and architecture.4,7 Additionally, while nomograms exist in an attempt to better risk stratify UTUC using similar clinical criteria,7 physicians also assess risk using cytology, biopsy, and imaging that have not been routinely incorporated into overall risk models. 

Characteristics of low-risk UTUC include low volume/low focality, small size (<2cm), low-grade cytology confirmed by biopsy, and no evidence of invasion on imaging.4 Although insufficient data exist to subclassify low risk UTUC, smaller, lower volume, unifocal papillary lesions likely represent the lowest biological risk; however, even in cases such as this, tumor location and intrarenal anatomy may affect therapeutic options increasing the risk of nephroureterectomy.

Managing low-risk UTUC

Given the complexities of endoscopic diagnosis and the management of low-risk UTUC, many clinicians resort to radical nephroureterectomy (RNU) early in patients deemed at low risk for immediate need for renal replacement. Unfortunately, among patients in the age demographic at risk for UTUC, up to 50% already demonstrate CKD stage 3 or higher.8 Despite this, 80% of those with low-risk UTUC undergo RNU as primary treatment.9 While this practice addresses the common risk of under staging seen in UTUC, it unfortunately underestimates the long-term consequences of CKD and the surgical risks in elderly patients with cancer. As many as 1 in 3 patients undergoing RNU suffer a complication,8 which has also been associated with a 25%-30% decline in eGFR.10 This decline may be even greater in those with pre-existing CKD stage 3 or higher. Importantly, current guidelines do not support the use of radical surgery (cystectomy) in untreated low-risk NMIBC, although more endoscopic and intravesical options exist for lower tract UTUC.

Evolving management paradigms

As mentioned previously, there is perceived uncertainty in assuming UTUC to be low risk given the endoscopic, pathologic, and radiographic limitations of current techniques. Based on this uncertainty, patients with adequate renal reserve are often defaulted to RNU unless they and their managing clinician deems that adequate endoscopic management of low-volume, low-grade papillary tumors is especially safe and feasible. The result may be loss of nephron mass for disease that did not require it. Given that 38%-50% of patients in this age demographic,11 and up to 57% of those with UTUC,12 already have CKD stage 3 with both kidneys in place, this additional loss in renal function renders most individuals ineligible for future cis-platinum-based therapy should their disease progress elsewhere, as well as adding to their co-morbidity burden.

Of greater clinical concern are those patients whose renal function is already markedly compromised and in whom radical nephrectomy poses a more substantial risk of dialysis that may exceed the oncologic risks of their low-grade UTUC. In these patients, repeated endoscopic management with intracavitary therapies via a retrograde or antegrade approach have been used, but no clear guidelines exist. 

Administration of bacillus Calmette-Guérin (BCG) into the upper tract has been by slow gravity antegrade drip or retrograde via a cystoscopically placed ureteral catheter. A far less reliable method used has been via reflux from the bladder into the upper tract via an indwelling stent. Each of these methods is inadequate due to (1) lack of dwell time, (2) uneven topical distribution in the renal calyces, pelvis and ureter, (3) higher risks of infection and systemic absorption compared with lower-tract administration, and (4) constant urine profuction making adequate dosing difficult.  Although administration of upper-tract BCG, or less commonly liquid chemotherapy, have been described with modest efficacy based on retrospective data, patient selection and physician experience are exceptionally heterogeneous. Current administration options are suboptimal, and standards are lacking, making upper-tract management with topical therapies for UTUC the exception rather than the rule.13

The recent development, testing, and approval of a reverse-thermal hydrogel-based delivery for mitomycin C (Jelmyto, UroGen Pharma) into the upper urinary tracts for low-risk UTUC offers the possibility of improved urothelial coverage, dwell, delivery, and chemoablation. In a recently published single-arm phase 3 open-label trial (OLYMPUS), 42 of 71 patients with low grade UTUC in the intent-to-treat population achieved a complete response, including 59% who were considered endoscopically unresectable.14 The most common adverse events seen included ureteric stenosis, urinary tract infection, hematuria, flank pain, and nausea. These data have led to a recent FDA approval and incorporation in the updated NCCN bladder cancer guidelines for UTUC.3

 In patients with positive cytologies, high-grade disease and/or high endoscopic or radiographic suspicion for high-risk UTUC, neoadjuvant chemotherapy is increasingly considered the standard of care given that at least 45% of patients will be cisplatin-ineligible following RNU.12,15 While no data from randomized controlled trials exist directly supporting neoadjuvant therapy for high-risk UTUC and the experience is largely extrapolated from phase 3 data in bladder cancer, there are level 1 data to support the use of adjuvant chemotherapy in UTUC. In the phase 3 POUT trial, adjuvant gemcitabine and cisplatin for patients with resected pT2-4N0-3M0 and adequate renal function resulted in improved progression-free survival compared with surveillance.16

Unmet needs and future directions 

There is growing recognition that UTUC is a biologically and clinically distinct entity requiring unique guidelines, algorithms, and expertise. Goals of therapy should include balancing oncologic and renal functional risks.  As new treatment options emerge, a refocus on nephron preservation for well-selected patients should be included in treatment paradigms for UTUC.

Marshall Strother, MD, Robert G. Uzzo, MD, MBA are affiliated with the Fox Chase Cancer Center in Philadelphia. Dr Strother is a first-year urologic oncology fellow. Dr Uzzo is the G. Willing “Wing” Pepper Chair in Cancer Research, Chairman of the Department of Surgery, and Professor of Surgery at Temple University School of Medicine in Philadelphia.

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