Management and Treatment Strategies for Upper Tract Urothelial Carcinoma: Current Insights

Introduction

Upper tract urothelial carcinoma (UTUC) is a relatively rare disease, accounting for 5–10% of all urothelial carcinoma (UC) with an estimated annual incidence of approximately two cases per 100,000 persons.¹ Despite this, the reported incidence has risen over recent decades; a trend attributed in part to improved diagnostic imaging and wider use of ureteroscopy, though a true increase in incidence independent of detection cannot be excluded.^2,3 Commonly observed risk factors include male sex, smoking, exposure to carcinogens, and hereditary disorders. Lynch syndrome, a genetic syndrome caused by mutations in mismatch repair genes, comprises approximately 10–20% of UTUC cases and presents in younger patients.² In patients with UTUC, the risk of recurrence in the bladder is approximately 25–50%, while the risk of recurrence in the contralateral upper tract is roughly 1–6%.^2,4,5

Despite growing knowledge of risk factors, the prognosis of UTUC is still closely associated with the stage and grade at presentation.^6,7 To determine the most optimal treatment, proper risk categorization and staging are essential.^4,5 However, this is a challenge, as proper staging is commonly limited due to difficulty in tissue sampling at diagnosis and imaging findings. Because of this, patients with UTUC often present with more advanced disease than patients with urothelial carcinoma of the bladder (UCB). Therefore, a broad array of surgical techniques is required to accurately manage or treat this disease.

As UTUC is a rare disease, much of our knowledge of treating UTUC is abstracted from UCB studies. Nevertheless, advancements in surgical technologies, such as ureteroscopes, ablative methods, robotic systems, and medical therapies, warrant new evaluations on this topic. The aim of this review is to synthesize the latest evidence on diagnosis and risk stratification, surgical techniques, and topical and systemic therapies in adult patients with non-metastatic and metastatic UTUC, with emphasis on oncologic outcomes, renal preservation, and emerging treatment paradigms.

Materials and Methods

This narrative review was conducted with a primary emphasis on surgical management of UTUC. A comprehensive literature search on studies published before September 2025 was performed using PubMed, MEDLINE, and EMBASE. Queries combined free-text keywords with Boolean operators (AND/OR/NOT) and controlled vocabulary (MeSH in PubMed; Emtree in Embase) for concepts including upper tract urothelial carcinoma (UTUC), endoscopic management, kidney-sparing surgery, chemotherapy, nephroureterectomy, immunotherapy, and imaging. We also reviewed contemporary AUA, EAU, and NCCN guidelines (accessed September 2025) and hand-searched reference lists of key articles. Articles were selected based on relevance to current surgical and perioperative practice, with preference given to randomized controlled trials, large multicenter cohorts, prospective studies, and contemporary guidelines. Conference abstracts were included when they represented the most current available data for ongoing trials or emerging modalities not yet published in full-text peer-reviewed format.

Diagnosis and Risk Stratification

For patients with suspected UTUC, AUA/SUO guidelines recommend cross-sectional imaging of the upper tract (UT) with contrast including delayed images of the collecting system and ureter. Barring any contraindications to its use, a multiphase computed tomography (CT) scan with excretory phase imaging of the urothelium or magnetic resonance (MR) urography is recommended.⁴ While current modalities demonstrate excellent accuracy in identifying local disease, challenges remain in identifying distant metastasis or recurrent disease. To address this issue, there is ongoing work in leveraging artificial intelligence (AI) and multiomics approaches to improve imaging and staging in UTUC. Multi-modal deep learning models that integrate multiphase CT imaging with clinical data have already demonstrated the potential for superior prognostic accuracy compared to imaging or clinical staging information alone.⁸ Recent developments in molecular imaging, such as positron emission tomography-CT (PET-CT) with novel tracers, are being further refined with AI-driven analytics to improve detection of lymph node metastases and distant disease. Advances in antibody-based PET tracers targeting specific tumor markers show evidence suggesting improved discernment and detection of lesions missed by standard imaging.⁹

Furthermore, integration of AI-enhanced urine cytology screening in combination with radiologist assessment has demonstrated the potential for improved sensitivity for muscle-invasive UTUC, increasing from 76.9% to 90.3%.¹⁰ While there are still challenges with standardization and clinical validation preventing implementation, AI-driven integration of multiomics and radiomics demonstrate great potential for increasing precision in diagnosis and prognosis.^11,12

Despite modern imaging modalities, initial staging of UTUC has historically been a challenging, with frequent clinical understaging and/or undergrading.⁹ Therefore, tumor characteristics observed by endoscopic techniques need to be taken together with cross-sectional imaging to assist in properly staging patients, which correlates with disease risk and helps steer management.^13,14 According to AUA guidelines, a standardized approach of classifying UTUC is required to capture clinical tumor features, including focality, appearance, and size, and radiographic features, including invasion, obstruction, and lymphadenopathy.⁴ Urine cytology can be combined with endoscopic biopsy to improve diagnostic yield and refine risk assessment. The sensitivity of detecting high-grade UTUC disease with urine cytology or ureteroscopic biopsy alone is 64.7% and 59.2%, respectively, while the combined sensitivity is approximately 85.7%.¹⁵ Therefore, guidelines recommend obtaining both biopsy and cytology when feasible. If ureteroscopy is not feasible, selective ureteral washings may be obtained instead.

Patients should be risk-stratified using a composite of findings based on prespecified characteristics such as tumor size, multifocality, high-grade cytology/biopsy, evidence of invasion on imaging, and presence of hydronephrosis (Table 1). Current guidelines recommend against inspection of a contralateral upper tract in the absence of abnormal clinical or radiographic findings due to risk of patient injury and tumor seeding.⁴

Table 1 Risk Classification from the AUA/SUO Guidelines

As part of risk stratification, every candidate for extirpative surgery should undergo a prior assessment of renal risk, including the probability of post-nephroureterectomy chronic kidney disease and risk of dialysis. Estimating postoperative glomerular filtration rate (eGFR) using baseline kidney function, contralateral renal anatomy, and anticipated ischemic/obstructive factors help match treatment intensity to patient physiology and supports shared decision-making regarding nephron-sparing options when oncologically appropriate (Figure 1).

Figure 1 Recommended treatment algorithm. (*In patients with solitary kidney, consider a more conservative approach).

Endoscopic Techniques

Endoscopic Management

Endoscopic management (EM) for UTUC has expanded with the advent of smaller, highly deflectable ureteroscopes, improved optics, dedicated instruments, and modern laser platforms.¹⁶ EM confers the advantage of being performed outpatient, with lower morbidity than invasive procedures.^17,18 Despite the conferred benefits, this approach does have anatomical considerations due to size constraints, particularly in ureteral tumors or when performing in retrograde fashion. Current AUA/SUO guidelines suggests endoscopic management such as retrograde ureterorenoscopy or antegrade ureterorenoscopy via percutaneous access with fulguration or ablation as the initial option for low-risk (LR) (typically <2 cm, unifocal, low-grade, noninvasive) disease. It may also be considered in select patients with low-volume tumors, bilateral disease, solitary kidney, poor renal function or patients unfit for radical nephroureterectomy (RNU).⁴ In practice, retrograde URS is most common, while antegrade access is favored for larger pyelocaliceal lesions (>1.5 cm) or anatomically challenging locations (eg., lower-pole calyx, prior urinary diversion) when retrograde access is limited.^4,5 When retrograde is chosen, a semirigid ureteroscope is commonly used for distal/mid-ureteral tumors, while a flexible ureteroscope is required for proximal ureteral, renal pelvis, and calyceal tumors. A ureteral access sheath can facilitate repeated scope passage and irrigation; however, its use should be judicious to avoid injury.¹⁷ A single-center retrospective study found the use of ureteral access sheaths was protective for bladder recurrence (39.7% vs 11.5%, p=0.01).¹⁹ This is thought to be due to decreasing downstream flow of tumor cells into the bladder, as well as decreased intrapelvic pressures that may reduce seeding through pyelovenous backflow. While more invasive than retrograde URS, percutaneous management allows for utilization of various larger-caliber tools that would normally face size-limitations from the ureter. This modality allows for rigid nephroscopy for efficient debulking, a flexible pyeloscope/cystoscope for complete calyceal inspection, antegrade flexible URS to survey the ureter, and resectoscope loop cautery when mass reduction is required.

Options for endoscopic management vary, including bulk excision with forceps or a basket, and resection to the base using various ablative laser modalities (Ho:YAG, Nd:YAG, Tm:YAG).²⁰ Of the laser modalities, Ho:YAG offers a shallow penetration of approximately 0.3–0.4 mm, making it well-suited for superficial ureteral tumors and minimizing thermal injury to deeper tissues. Alternatively, Nd:YAG offers a deeper penetration up to 3–6mm, making it better suited to bulkier tumors, but less ideal for ureteral tumors due to the higher chance of complications from collateral thermal injury.^21,22 The Tm:YAG offers a very short penetration of approximately 0.1–0.2 mm, with its energy profile suited for hemostasis, and is gaining in popularity.^23–25

Despite widespread availability, comparing outcomes between lasers is challenging, as studies frequently may not have uniform laser settings and approaches. Tm: YAG was previously shown to experience a 10.5–38% postoperative complications rate, while complications were listed as mostly mild and transient in nature. Major events involving laser ablation include ureteral strictures and occasional obstructive renal failure requiring stent placement, but were extremely rare with rates less than 2%.²⁶ Beyond clinical safety, there is some evidence that EM can impose greater procedural burden, with more anesthesia time and higher overall costs versus radical surgery.²⁷ However, RNU may actually be more costly overall when accounting for procedural expenditures, readmissions, and long-term CKD management, averaging USD 252,272 per patient more in 5 years.¹⁸ Historically, logistic challenges such as anatomic constraints, specialized equipment, and visualization challenges inherent to endoscopy with irrigation, serve as barriers to adoption, although newer platforms continue to address these issues.²⁸ Overall, EM is a reasonable option, particularly in low-grade, non-bulky tumors, and select patients with certain comorbidities.^4,5

Intracavitary Therapy

Due to the high recurrence risk and difficulty in completely treating certain upper tract tumors, adjuvant intracavitary therapies have been investigated to address this issue. However, intracavitary therapies face barriers to efficacy due to the short dwell times in the upper tracts. In response, recent advances leading to increased dwell times and longer exposure of a drug with the tumor target potentially offer improved recurrence-free intervals. The OLYMPUS trial, a Phase III, multicenter study, evaluated treating primary or recurrent low-grade UTUC measuring between 5–15 mm with a reverse thermal gel containing mitomycin (UGN-101, 4 mg mitomycin JELMYTO, UroGen Pharma).²⁹ The medication is instilled either retrograde or antegrade into the upper tract as a liquid under chilled conditions, which is subsequently converted to a semisolid gel depot at body temperature. This conversion increases the dwell time of the drug to 4–6 hours, with complete response reported in 59% of patients at primary evaluation, and 84% durability at 12 months.²⁹ UGN-101 has also been used in the chemoablative setting, however the complete response (CR) was higher in patients with smaller tumors rather than the adjuvant setting (69% vs 37% response, p<0.001).³⁰ Ureteral stenosis was the most common treatment-associated adverse event in the OLYMPUS trial, reported in up to 44% of patients when including all grades of ureteric obstruction, with higher number of instillations corresponding with an increased incidence of stenosis.²⁹ The retrograde approach used for instillation was thought to be a significant contributor, and patients who underwent instillation through an antegrade approach had higher CR rates and lower rates of strictures. Risk factors for post-instillation stricture include ureteral tumor location, repeated instrumentation, and higher instillation counts. Given the frequency of this complication, clinicians should perform upper tract imaging and ureteroscopy at scheduled follow-up intervals to monitor for stricture development. Of note, updated long-term data from the OLYMPUS study demonstrated a median duration of response of 47.8 months among complete responders, and 75% of patients with sustained CR at 12 months remained recurrence-free at a median follow-up of 53.3 months, with no patients progressing to high-grade disease.²⁹ UGN-101 remains the only FDA approved therapy for select patients with low-grade UTUC.

Intracavitary Bacillus Calmette-Guerin (BCG) is indicted for patients with carcinoma in situ (CIS) of the upper tract or HR favorable UTUC who may not be candidates for radical therapy following EM. Although the results of treating CIS of the UT with BCG remain promising, the data for other HR UTUC disease appears to be inferior to radical surgery and should only be reserved for select cases, such as solitary kidney, concurrent contralateral disease, or risk of progression to ESRD.^31,32 In HR patients, including CIS of the upper tract, AUA/SUO guidelines state induction BCG may be offered to those with HG non-invasive disease who underwent EM.^4,33 Of note, these recommendations are based on expert opinion rather than existing evidence. Instillation can be performed via percutaneous nephrostomy tube, retrograde ureteral catheter, or through vesicoureteral reflux with a stent in place. Drug-eluting stents and other novel delivery systems are in development but have not made it into clinical practice yet.

Although endoscopic ablation and intraluminal instillations have remained the most common kidney-sparing modalities, new treatments are currently under investigation. Photodynamic therapy is a newly investigated modality showing great promise in treating low-grade disease. Padeliporfin (brand name TOOKAD), a vascular-targeted photodynamic (VTP) therapy combines an intravenous molecule with a non-thermal laser therapy through ureteroscopy in the treatment of low-grade UTUC.³⁴ Once activated, padeliporfin triggers the production of high levels of radical oxygen species, which cause destruction of the blood vessels supplying the tumor followed by rapid death of tumor cells.³⁵ The procedure can be performed in an outpatient, is minimally invasive, and spares the kidney from any significant injury. The ENLIGHTED Trial, a Phase 3, single arm, non-randomized, multicenter trial evaluating the safety and efficacy of padeliporfin VTP therapy, is currently enrolling patients.³⁴ The interim results from 37 patients demonstrated approximately 87% response with a 73% CR, and a serious adverse event rate (Clavien-Dindo complication 3 or greater) of 9%.³⁶

Follow Up

While EM carries the benefit of renal preservation, it does carry a higher risk of recurrence and demands frequent surveillance. Management is stratified by the initial risk category, with LR groups requiring a first-look cystoscopy and ureteroscopy within 3 months. In LR patients, guidelines recommend cystoscopy and upper tract imaging every six to nine months for the first two years, then at yearly intervals, with imaging based on shared decision making (SDM) after five years. HR patients must undergo closer surveillance, with cytology added on to first-look cystoscopy and ureteroscopy. Surveillance cystoscopy, cytology, and UT imaging should be done every three to six months for the first three years, then annually afterwards. Regardless of risk, EM managed patients should also undergo ureteroscopy at sixth months and one year. After five years of surveillance, ongoing surveillance can be based on SDM making. Early detection of recurrences allows for repeat ablation and further renal preservation.⁴ The guidelines for optimal surveillance are based on expert opinion and retrospective series, as no prospective randomized trials have been conducted to define the optimal surveillance intervals or modalities in this population.³⁷

It should be recognized that EM, while less morbid than extirpative surgery, imposes a substantial surveillance burden on patients and healthcare systems.²⁷ The requirement for serial ureteroscopy, cross-sectional imaging, and cytology over a period of at least five years may result in greater cumulative procedural exposure, anesthesia events, and associated costs than a single radical surgery.²⁷ Shared decision-making should incorporate the patient’s willingness and ability to adhere to a surveillance protocol, as well as access to centers with expertise in ureteroscopic management, when considering EM as the primary treatment modality.

Outcomes

EM provides durable oncologic control and high renal preservation in well-selected LR UTUC. In LG, noninvasive UTUC, EM achieves 5-year DSS rates of 88–97% and OS rates of 59–85%.^27,38,39 In a pooled analysis of 1091 patients over 21 studies, the bladder recurrence rate was 35% after retrograde endoscopic surgery and 17.7% after antegrade endoscopic surgery. The pooled UTUC recurrence rate was 56.4% after retrograde endoscopic surgery and 36.2% after antegrade endoscopic surgery. While the antegrade approach benefits from lower risk of seeding, appropriate nephrostomy placement increases the cost and risks of this approach.⁴⁰ Ipsilateral recurrence rates are high, ranging from 50–68% with most occurring within 2–3 years.^41,42 Progression to muscle-invasive or metastatic disease is less common, with rates around 30% and 15%, respectively.^27,41 HG tumors undergoing EM have inferior oncologic outcomes and higher risk of progression, and thus should be reserved for imperative indications in these patients. The 5-year renal preservation rates range between 71% and 83%.^27,38,39 About 20% of patients will require progress to RNU due to high rates of ipsilateral recurrence, disease progression, anatomical challenges, patient preference, and adverse events to treatment (strictures or bleeding).

Radical Surgery

Segmental Ureterectomy

Distal ureterectomy (DU) with bladder cuff excision (BCE) and ureteral reimplant is the preferred treatment option for HG ureteral tumors localized to the distal ureter. Reimplantation may require a psoas hitch or boari flap to allow for a tension-free anastomosis. Additionally, in patients with HG mid-ureteral tumors, segmental ureterectomy (SU) may be considered but may require an ileal ureter for reanastomosis. Distal or segmental ureterectomy may be required in select cases of bulky LG ureteral tumors due to difficulty in EM and concern of under-treatment.

Radical Nephroureterectomy

Despite advances in EM and kidney sparing surgery, RNU with BCE on and lymph node dissection (LND) remains the gold standard for management of HR UTUC of the mid and upper ureter and pyelocaliceal system, or LR but endoscopically unmanageable disease. Open nephroureterectomy (ONU) can be done in a one (flank-to-lower abdominal incision or midline incision) or two (flank incision for the kidney and proximal ureter, and lower abdominal incision such as a Gibson or Pfannenstiel, for the distal ureter and bladder cuff) incision technique.⁴³ Regardless of technique, core principles remain with complete excision of ipsilateral upper tract urothelium, including the intramural portion of the ureter and ureteral orifice with negative margins, and avoidance of urinary spillage, such as by early low ligation of the ureter, to minimize the risk of seeding urothelial cancer outside the urinary tract. According to AUA/SUO guidelines, open, robotic, and laparoscopic approaches are suitable for RNU so long as the above oncologic and surgical principles are followed.⁴ However, there has been a marked shift towards minimally invasive techniques over the decades, with utilization increasing from 29% to 72%, while seeing a decline in ONU over the same period.⁴⁴ For RANU, the multiport (MP) approach is the most common, with historical outcomes comparisons being based on this modality.

Minimally invasive nephroureterectomy (MINU) does seem to confer some perioperative advantages over ONU, being associated with a lower 60-day complication rate, (19% vs 23% with ONU) and shorter length of stay (mean 3.3 vs 4.3 days), and reduced intraoperative blood loss.^44,45 Other studies seem to reinforce a reduction in blood loss and hospital stay, while demonstrating similar rates of complications.⁴⁶ In a retrospective review of a large claims database, Franco et al found that ONU independently predicted complications (OR 1.33, 95% CI 1.20–1.48). While readmission rates were similar, cost analyses favored MINU, with overall 60-day expenditures and inpatient costs lower than ONU.⁴⁴ However, these studies were likely limited by selection bias, with more advanced cases undergoing ONU. In a three-center series of ≥pT2/high-grade UTUC, laparoscopic nephroureterectomy (LNU) and ONU had comparable OS, RFS, and CSS, but of note, instances of peritoneal carcinomatosis occurred only after laparoscopy (6.3%).⁴⁷

Lymphadenectomy

LND is a vital component of surgical management of UTUC, particularly in HR disease. Current AUA and NCCN guidelines support regional LND at the time of RNU or SU for HG or locally advanced disease, as it improves staging accuracy and may confer oncologic benefit. The location of LND is based on tumor location: for renal pelvis tumors, dissection should extend from the renal hilum to the inferior mesenteric artery; for proximal ureteral tumors, from the renal hilum to the aortic bifurcation; and for distal ureteral tumors, ipsilateral pelvic LND including obturator and external iliac nodes.^4,5 However, the therapeutic benefit remains controversial, particularly in clinically node negative disease. A large multicentered analysis utilizing the ROBUUST (Robotic surgery for Upper Tract Urothelial Cancer Study) registry analyzed patients who underwent LND with negative lymph nodes, those who underwent LND with positive lymph nodes, and those who did not undergo LND. This study found that although removing positive lymph nodes did not confer an improved OS, a LND yield ≥10 in clinically node negative disease was associated with improved RFS.⁴⁸ Due to the limitations in accurate staging on imaging, LND remains the gold standard for lymph node staging.

Intravesical Therapy

Intravesical recurrence is common following RNU or SU for UTUC, with rates ranging between 22–47%.^49–52 Guidelines recommend a single dose of perioperative intravesical chemotherapy (most commonly gemcitabine or mitomycin is used) for eligible patients.⁴ Currently, there is no consensus on superiority of one intravesical agent over another. This recommendation is supported by two prospective randomized trials (the THP Monotherapy Study Group Trial and the ODMIT-C trial) demonstrating a significant reduction in intravesical recurrence following a single perioperative instillation.^53,54 In a recent systematic review of 2483 patients, Moretto et al demonstrated intravesical chemotherapy significantly reduced the risk of intravesical recurrence at 12 months (OR = 0.46; 95% CI: 0.33–0.65; P < 0.001) and at 24 months (OR = 0.41, 95% CI: 0.28–0.61; P < 0.001). Interestingly, no association was found when contrasting intraoperative and postoperative instillations (OR = 0.66; 95% CI 0.34–1.28; P = 0.2), nor single vs. multiple instillation (OR = 1.37; 95% CI: 0.75–2.50; P = 0.3). Unfortunately, with a lack of power or homogenous data, a definitive opinion on timing of intravesical therapy cannot be determined.⁵⁵ Although most studies and guidelines recommend administration within 24–48 hours postoperatively, some centers will instill the intravesical therapy during foley removal, once a cystogram confirms complete bladder integrity. Regardless of timing, complication rates of intravesical chemotherapy remain low, with minor complications under 10% and major complications less than 1%.⁵⁵

Interestingly, there is continued interest in alternative methods to prevent intravesical recurrence. Yamamoto et al reported significantly lower bladder recurrence with intraoperative irrigation with normal saline or distilled water compared to no irrigation (25.0% vs 52.5%, median follow-up 26.1 months), which may suggest that just the function of irrigating the bladder following RNU or SU can significantly reduce recurrences from tumor seeding. However, this study was also biased with heterogeneity in technique and unmeasured confounding, therefore a more robust study is needed before any changes in practice can be suggested.⁵⁶

Follow Up

Follow up after RNU is essential due to high risk of recurrence in the bladder or outside. Therefore, follow up schedules are risk-adapted based on pathologic stage, grade, and surgical approach.^4,5 For patients with non-muscle invasive disease (<pT2, N0/M0), a cystoscopy with cytology should be done at three months, then tailored by grade. Surveillance cystoscopy with cytology should be repeated in LG patients at least every 6–9 months for years 0–2, then at least annually; HG should undergo at least every 3–6 months for the first three years, then at least annually. Due to the ongoing risk of metastasis and contralateral disease, cross-sectional imaging (preferably multiphasic CT urography) should be obtained within six months of surgery and then at least annually for ≥5 years. For muscle invasive (≥pT2Nx/N0) disease, patients should undergo cystoscopy with cytology at three months, then every 3–6 months for three years and annually thereafter. CT urography should be obtained every 3–6 months in years 1–2, every six months in the third year, and annually through year five, plus chest imaging (ideally CT) every 6–12 months for five years. Beyond five years without recurrence, continue or de-escalate via SDM.⁴

Outcomes

Studies have shown that the 5-yr CSS is approximately 61.5–89.9% and the 5-yr RFS was 59–82.1% after radical nephroureterectomy.⁵⁷ Not surprisingly, tumor stage and grade are the most significant prognostic factors for recurrence and survival, with most recurrences occurring with 2 years postoperatively. Multiple studies demonstrated comparable 5-year RFS, MFS, CSS, and OS between SU and RNU, all while significantly preserving renal function.^58–61 However, some of these studies found that compared to RNU, SU had a modest increased risk of intravesical recurrence.^58–61

There is no high-quality prospective data comparing open versus minimally invasive approaches for management of UTUC. The available data from retrospective studies show somewhat mixed results, with the data trending towards better disease control with open approaches (Table 2).^44,62–67 Overall, there was no significant difference in CSS or OS individually between ONU, LNU and robot-assisted nephroureterectomy (RANU). However, several of the studies did find that LNU and RANU had statistically worse intravesical RFS, while other studies demonstrated differing results.^62–64,66 The heterogeneity observed across these studies is likely driven by the retrospective nature of all available comparisons, selection bias in surgical approach assignment, and variation in bladder cuff excision technique, which has been shown to significantly influence intravesical recurrence rates.⁶⁸ No prospective randomized trial comparing open versus minimally invasive RNU has been conducted, and definitive recommendations regarding surgical approach selection cannot be made on the basis of existing retrospective data. The perioperative advantages of MINU, including reduced blood loss, lower complication rates, and shorter hospitalization, may be particularly relevant for elderly or comorbid patients, while an open approach may merit consideration in locally advanced (≥pT2) disease.

Table 2 Survival Outcomes of Studies Comparing Open vs MIS Approaches for RNU

Single Port

RANU with MP is the most-utilized approach for radical surgery, with extensive experience confirming the outcomes of this method. However, single port (SP) platforms are being investigated, with interest in the potential to facilitate cross-quadrant work through a single incision, which may simplify distal ureter and bladder-cuff management.⁷¹ Additionally, an SP retroperitoneal approach may provide certain advantages such as restricting bleeds, urine leaks, and tumor seeding to a confined space, such as the retroperitoneum.⁷² In a single-institution case series 20 patients, Bang et al described a retroperitoneal SP RANU with bladder cuff excision for UTUC. No perioperative complications were reported, with half of the patients receiving an LND. After six months of follow up, only one patient reported recurrence in the bladder.⁷² This initial report on feasibility suggests that SP RANU may streamline multi-quadrant access with acceptable short-term perioperative outcomes. However, this study was limited by its small, single-surgeon design, lack of comparator, and short follow-up, leaving us with no information on oncologic outcomes.

Systemic Therapies

Neoadjuvant Therapy

A summary of major clinical trials relevant to UTUC management is presented in Table 3. Current guidelines recommend neoadjuvant chemotherapy with patients with UTUC, particularly those with higher stage and/or grade tumors or concerning radiographic findings. Although there are no randomized-controlled studies, multiple prospective studies have demonstrated pathologic response rates, downstaging, and improved survival outcomes with platinum-based neoadjuvant chemotherapy compared RNU alone.^73–76 The rationale for neoadjuvant chemotherapy is the high risk of postoperative renal decline, which may preclude adjuvant platinum-based chemotherapy. Loss of a renal unit following RNU results in a significant decline in glomerular filtration rate, with studies demonstrating that up to 85% of patients become cisplatin-ineligible postoperatively.⁷⁵ Therefore, preoperative assessment of cisplatin eligibility is essential, and patients who are candidates for platinum-based therapy should ideally receive neoadjuvant chemotherapy before RNU while bilateral renal function is preserved. The most commonly used neoadjuvant regimens are split-dose gemcitabine-cisplatin (GC) and dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (ddMVAC). In a systematic review, neoadjuvant chemotherapy demonstrated pathologic response in 43% and downstaging in 33% of patients, resulting in improvement in oncologic outcomes compared to RNU alone.⁷⁷

Table 3 Summary of Major Clinical Trials in UTUC Management

Breakthroughs in immunotherapies for urothelial cancers have occured, but there is a paucity of data regarding their efficacy in the neoadjuvant setting. A small Phase II study (PURE-02) evaluating neoadjuvant pembrolizumab in high-risk UTUC with only 10 patients included showed no pathologic response, therefore there is no evidence to support the use of neoadjuvant immunotherapy for high-risk UTUC at this time.⁸⁵ However, neoadjuvant chemo-immunotherapy combinations have shown more promising results. The iNDUCT trial, the first completed UTUC-specific neoadjuvant chemo-immunotherapy study, evaluated durvalumab combined with gemcitabine-platinum in 49 patients with high-risk UTUC, demonstrating pathologic downstaging (≤ypT1) in 42–50% of patients depending on platinum regimen.⁸⁶ The rationale for combining chemotherapy with checkpoint inhibition is based on the premise that platinum-based agents may promote antitumor immunity, thereby enhancing susceptibility to checkpoint blockade in otherwise immune-cold tumors.⁸⁷ Further UTUC-specific neoadjuvant combination trials are ongoing.

Adjuvant Therapy

Adjuvant therapy is the standard of care for eligible patients with HR UTUC following RNU, particularly in patients with pT2-4 or pN+ disease. The POUT trial, the only randomized Phase III UTUC clinical trial, evaluated adjuvant platinum-based chemotherapy after RNU in patients with locally advanced UTUC (either pT2-T4 pN0-N3 M0 or pTany N1-3 M0).⁷⁸ Patients were randomized to platinum-based chemotherapy based on eligibility (cisplatin, or carboplatin for glomerular filtration rate <50 mL/min) with gemcitabine for 4 planned adjuvant cycles. At 5-year follow up, platinum-based adjuvant therapy demonstrated an improvement in disease-free survival (DFS) (63% vs 46%; HR 0.54; CI: 0.36–0.79) and metastasis-free survival (MFS) (19% improvement; HR: 0.55; CI: 0.36–0.77).⁷⁸ The study demonstrated a trend towards overall survival benefit but was too underpowered to detect it.

In patients who received neoadjuvant platinum-based chemotherapy, those with residual high-risk disease (ypT2-4 or ypN+), or those ineligible for adjuvant platinum-based chemotherapy, can consider adjuvant immunotherapy. The evidence for adjuvant immunotherapy is derived from CheckMate 274 and Ambassador trials, two adjuvant, predominantly bladder cancer, trials.^81,83 However, in these trials, UTUC did not derive DFS benefit from adjuvant immunotherapy on subgroup analysis. Despite this, guidelines recommend discussing adjuvant nivolumab in those with residual HR disease after neoadjuvant chemotherapy or for cisplatin-ineligible patients. Clinical trials evaluating the role of adjuvant combination or targeted therapies in patients with UTUC are ongoing.

Adjuvant radiation therapy has been studied for loco-regional control in patients with advanced UTUC after radical resection, however the findings are mixed without a clear oncological benefit.⁸⁸

Metastatic Disease

Platinum-based chemotherapy has been the standard of care for metastatic UTUC for more than 30 years, with objective response rates approaching 50%. However, most patients experience progression within a year. In 2023, EV-302, a phase III randomized multi-institutional clinical trial, compared enfortumab vedotin (EV), a nectin-4 antibody–drug conjugate, in combination with pembrolizumab versus platinum-based chemotherapy. The study demonstrated significant improvement in progression-free survival (PFS) (HR 0.45; CI 0.38–0.54) and OS (HR 0.47; CI 0.38–0.58), with a median overall survival improvement of 31.5 vs. 16.1 months.⁷⁹ The survival benefit was demonstrated regardless of cisplatin eligibility and in both bladder cancer and UTUC. Based on the results of EV-302, the FDA approved the combination of enfortumab vedotin and pembrolizumab as first-line therapy for locally advanced or metastatic urothelial carcinoma, establishing a new standard of care. However, while patients with UTUC comprised 27% of the study population, no specific subgroup analysis was carried out to look at outcomes unique to upper tract disease, and the applicability of these results to UTUC warrants further investigation. For patients ineligible for or who progress on EV with pembrolizumab, systemic platinum-based chemotherapy remains standard of care. The CheckMate 901 trial, a phase III randomized control trial demonstrated an overall survival benefit (median OS 21.7 vs 18.9 months; HR 0.78; CI 0.63–0.96) with the addition of nivolumab to platinum-based chemotherapy.⁸⁰ Similar to other trials, patients with UTUC were included in the trial, but no subgroup analysis for UT patients was performed. For patients with complete, partial, or stable response on first-line platinum-based chemotherapy, avelumab maintenance significantly prolongs overall survival (HR 0.69; CI 0.56–0.86) compared to best supportive care.⁸⁹ Unfortunately, while many of the trials regarding avelumab report including UTUC patients, none report subgroup analysis specific to this disease.⁹⁰ For patients that are unfit for combination therapy, single agent pembrolizumab or atezolizumab are used.^81,84 Third-line therapies include single-agent EV, sacituzumab govitecan, and erdafitinib.³³ For patients harboring FGFR2/3 fusions or FGFR3 mutations, erdafitinib is an approved option based on the phase III THOR trial, which demonstrated improved OS compared to chemotherapy (12.1 vs 7.8 months; HR 0.64; p=0.005) in patients with FGFR-altered metastatic urothelial carcinoma who had progressed on prior anti-PD-(L)1 therapy.⁸² Notably, FGFR3 alterations are more prevalent in UTUC than in bladder UC, occurring in approximately 25–54% of upper tract tumors, which positions FGFR-directed therapy as a particularly relevant strategy in this population.⁸⁷

While these advances represent a significant improvement in outcomes, practical considerations warrant discussion. The combination of enfortumab vedotin and pembrolizumab carries substantial cost, and access may be limited in resource limited settings or regions without established infusion infrastructure. Similarly, novel targeted agents such as erdafitinib require companion diagnostic testing, adding cost and logistical considerations to the treatment pathway. These factors should be taken into account when counseling patients regarding available treatment options.

An important limitation of the current evidence base for systemic therapy in UTUC is the reliance on data derived predominantly from bladder cancer trials. While patients with UTUC comprised a meaningful proportion of enrollment in several landmark studies, including approximately 27% in EV-302, 21% in CheckMate 274, and 22% in AMBASSADOR, UTUC-specific subgroup analyses were either not performed or underpowered to detect meaningful differences in outcomes.^79,81,83

Future Directions

Circulating tumor DNA (ctDNA) and liquid biopsy technologies are rapidly advancing as noninvasive tools for the diagnosis surveillance of UTUC. Recent studies have demonstrated that individualized ctDNA monitoring using digital PCR and next-generation sequencing can detect tumor-specific mutations in plasma and urine, accurately corresponding with tumor burden, and are able to detect recurrence faster than traditional methods by weeks to months.^91,92 A recent prospective study demonstrated the utility of preoperative ctDNA, with a sensitivity and specificity for muscle-invasive and non-organ-confined UTUC exceeding 70%, with good prognostic value for PFS and CSS.⁹³ Additional biomarkers derived from liquid biopsy such as cell-free DNA (cfDNA) have shown that elevated levels post-nephroureterectomy are significant predictors of tumor progression and cancer-specific survival, while circulating tumor cells (CTCs) have shown promise in diagnosis and surveillance.^94,95

High-sensitivity ctDNA assays are now commercially available, capable of detecting molecular residual disease with specificity approaching 98–100% in urothelial carcinoma, and are being prospectively validated trials.⁹⁶ However, CTC detection in localized UTUC remains suboptimal, with detection rates as low as 35% in early-stage disease. Current clinical guidelines do not endorse routine use of liquid biopsy for UTUC diagnosis or surveillance due to insufficient prospective validation and current technical constraints.⁹⁷ Beyond the lack of prospective validation, practical barriers to implementation include the significant cost of commercially available ctDNA assays, which may exceed several thousand dollars per test, the lack of standardization across platforms, and the absence of evidence demonstrating that ctDNA-guided treatment adjustments improve outcomes in UTUC.

In summary, ctDNA and liquid biopsy are promising for noninvasive diagnosis, risk stratification, and recurrence monitoring in UTUC, with recent clinical trials supporting their prognostic and diagnostic utility. As these technologies continue to develop, they may provide a major improvement in cost and utility compared to traditional surveillance methods.

Conclusion

UTUC is a rare, but aggressive malignancy that requires careful evidence-based and risk-adapted management. Radical nephroureterectomy with bladder cuff excision and lymph node dissection remains the standard of care for high-risk disease, supported by evidence from the POUT trial demonstrating improved disease-free survival with adjuvant platinum-based chemotherapy in locally advanced cases. Endoscopic management remains a viable option for low-risk and select high-risk patients, with long-term data from the OLYMPUS trial supporting the durability of chemoablation with UGN-101 in low-grade disease. In the metastatic setting, the combination of enfortumab vedotin and pembrolizumab has established a new standard of care based on the EV-302 trial, though UTUC-specific subgroup data remain limited. Emerging modalities, including padeliporfin vascular-targeted photodynamic therapy and liquid biopsy-based surveillance, have demonstrated promising early results but remain investigational. Interim data from the ENLIGHTED trial are encouraging, however firm changes in clinical practice should await completion of the trial and further prospective validation. Future efforts should focus on UTUC-specific clinical trials, improved risk stratification through molecular profiling, and the integration of novel biomarker technologies into surveillance paradigms to refine patient selection and optimize outcomes.