Upper Urinary Tract Urothelial Cell Carcinoma

7. DISEASE MANAGEMENT

All patients with suspicion of UTUC based on radiology, cystoscopy and urine cytology should be discussed in a multidisciplinary team prior to diagnostic ureteroscopy and the initiation of treatment [148]. This is supported by population-based data reporting increased use of invasive diagnostic modalities in hospitals with lower case-load [147].

7.1. Low-risk disease

7.1.1. General considerations on kidney-sparing surgery

Kidney-sparing surgery for low-risk UTUC reduces the morbidity associated with RNU (e.g., loss of kidney function), without compromising oncological outcomes [149]. In low-risk cancers, kidney-sparing surgery is the preferred approach as survival is similar to that after RNU [149,150]. This option should therefore be discussed in all low-risk cases, irrespective of the status of the contralateral kidney, in a shared-decision making process with the patient. Recommendations for kidney-sparing management of UTUC are listed in Section 7.1.7.

7.1.2. Ureteroscopy

Endoscopic ablation should be considered in patients with low-risk cancer [151,152]. A flexible ureteroscope is useful in the management of pelvicalyceal tumours [153]. The patient should be informed of the need and be willing and able to comply with an early second-look URS [154] and stringent surveillance; complete tumour resection or destruction is necessary [154]. Nevertheless, a risk of disease progression remains with endoscopic management due to the suboptimal performance of imaging and biopsy for risk stratification and tumour biology [155]. A systematic review reported comparable survival outcomes after endoscopic treatment to RNU at the cost of higher local recurrence rates and repeated interventions, but also with some uncertainties about long-term renal preservation after endoscopic treatment [156].

Tumour ablation of UTUC during URS is typically performed using holmium and/or thulium lasers, which allow tumour resection while minimising damage. The procedure involves direct visual identification of the tumour, followed by laser vaporisation or excision, and is often followed by meticulous irrigation to ensure no residual tumour fragments remain.

Second-look URS after initial endoscopic treatment is recommended in the conservative management of UTUC to ensure complete tumour resection and evaluate residual disease. Second-look URS should be performed within eight weeks following initial endoscopic treatment to assess for residual tumours or recurrence [154]. Other studies reported that up to nearly 50% of patients showed residual or recurrent disease during the second-look procedure, emphasising the value of early follow-up [157]. Therefore, early second-look URS plays a crucial role in optimising the outcomes of conservative treatment in UTUC by ensuring thorough tumour control.

7.1.3. Percutaneous access

Percutaneous management can be considered for low-risk UTUC in the renal pelvis [151,158]. This may also be offered for low-risk tumours in the lower caliceal system that are inaccessible or difficult to manage by flexible URS. However, this approach is being used less due to the availability of improved endoscopic tools such as distal-tip deflection of recent ureteroscopes [152,158]. Moreover, a risk of tumour seeding remains with percutaneous access [158].

7.1.4. Ureteral resection

Segmental or distal ureterectomy and ureteral resection with adequate margins, ideally based on frozen section analysis, provides sufficient pathological specimens for staging and grading while preserving the ipsilateral kidney. Further direct anastomoses using either an end-to-end technique or ureteroneocystostomy are usually performed but ileal-ureteral substitution or renal autotransplantation are also technically feasible depending on the length of ureter removed [159,160]. Segmental resection of the proximal two-thirds of ureter is associated with higher failure rates than for the distal ureter [161,162]. Distal ureterectomy with ureteroneocystostomy for tumours in the distal ureter is reported with a low cumulative incidence of ipsilateral upper tract recurrence (0-18%) [163-165] compared to 25-85% after endourologic kidney sparing [156].

7.1.5. Chemo-ablation

A single-arm phase III trial including 71 patients with biopsy-proven low-grade UTUC measuring less than 15 mm showed that the use of mitomycin-containing reverse thermal gel (UGN-101) instillations (6 weekly induction) in a chemoablation setting via retrograde catheter to the renal pelvis and calyces was associated with a complete response rate in a total of 41 patients (58%) [166]. The most frequently reported all-cause adverse events (AEs) were: ureteric stenosis in 31 (44%), urinary tract infection in 23 (32%), haematuria in 22 (31%), flank pain in 21 (30%) and nausea in 17 (24%), while 19/31 (61%) reported ureteric stenosis requiring treatment. Among patients with complete response, 29/41 (71%) received at least one maintenance instillation (median of 6), and 23/41 (56%) remained disease free at one year [166].

7.1.6. Adjuvant instillations

7.1.6.1. Upper urinary tract

The antegrade instillation of BCG or mitomycin C in the upper urinary tract via percutaneous nephrostomy after complete tumour eradication has been studied for CIS after kidney-sparing management [167,168]. Retrograde instillation through a single-J open-ended ureteric stent is also used. Before both the antegrade and retrograde approach a nephro-ureterogram needs to rule out ureteric obstruction or leakage, asses that there is no infection and ensure a low-pressure system to avoid pyelovenous influx during instillation/perfusion. The reflux obtained from a double-J stent has been used but this approach is suboptimal because the drug often does not reach the renal pelvis [169-172].

A systematic review and meta-analysis assessing the oncologic outcomes of patients with papillary (Ta-T1) UTUC or CIS of the upper urinary tract treated with kidney-sparing surgery and adjuvant endocavitary therapies (i.e., chemotherapeutic agents and/or BCG) did not find any difference between the method of drug administration (antegrade vs. retrograde vs. combined approach) in terms of recurrence, progression, CSS, and OS; however, all included studies were underpowered and highly heterogeneous. Furthermore, the recurrence rates following adjuvant instillations are comparable to those reported in the literature in untreated patients, questioning their efficacy [173]. The analyses were based on retrospective small studies suffering from publication and reporting bias.

Further evidence suggests that early single adjuvant intracavitary upper tract instillation of mitomycin C in patients with low-grade UTUC might reduce the risk of local recurrence [174]. The authors report limited complications related to the instillations and confirm the need for a retrograde pyelography before instillations are commenced to exclude contrast extravasation.

7.1.6.2. Bladder

There are currently no data to support the use of bladder instillation of chemotherapy after kidney-sparing surgery as available RCTs included only patients who received RNU.

7.1.7. Recommendations for kidney-sparing management of localised low-risk UTUC

7.2. Localised high-risk disease

7.2.1. Radical nephroureterectomy

7.2.1.1. Surgical approach

Although the open approach has long been standard [13], laparoscopic and robot-assisted RNU can both be used to treat high-risk UTUC, providing peri-operative benefits such as decreased risk of complication and shorter hospital stay [175-178]. In addition, equivalent oncological outcomes have been reported between the three procedures [175-177,179-183], except for a higher risk of intravesical recurrence after robotic RNU [184]. It is noteworthy that, although laparoscopic RNU was historically purported to provide inferior oncological outcomes [185], with higher risk of retroperitoneal dissemination or trocar metastases [186,187], in locally-advanced UTUC, this was not confirmed with the use of robotic RNU [184].

A meta-analysis of six retrospective comparative studies, showed that the use of a retroperitoneal vs. transperitoneal route at the time of laparoscopic RNU provides similar peri-operative and oncological outcomes, except for a longer operative time and shorter recovery time to bowel function [188]. Similarly, retroperitoneal robotic RNU is safe and feasible [189].

Regardless of the approach, RNU must be performed according to oncological principles to prevent tumour seeding:

1. Perform en bloc removal of the kidney, ureter and bladder cuff.
2. Avoid entering the urinary tract, except when performing a bladder cuff excision and only after prior clipping of the ureter and complete drainage of the bladder.

7.2.1.2. Bladder cuff management

Resection of the distal ureter and its orifice is performed because there is a considerable risk of tumour recurrence in this area and in the bladder [27,161,190-192]. Several techniques have been considered to simplify distal ureter resection, including the pluck technique, stripping, transurethral resection of the intramural ureter, and intussusception. None of these techniques have convincingly been shown to be equal to complete bladder cuff excision [28,190].

7.2.1.3. Lymph node dissection

There is no high-level evidence to support the use of LND for upper tract tumours. However, template-based and completeness of LND may improve CSS and reduce the risk of local recurrence [193]. Even in clinically [194] and pathologically [195] node-negative patients, LND may improve survival. Given that the risk of LN metastasis decreases with lower tumour stage [196], LND is likely unnecessary in patients with Ta/T1 UTUC [197-200]. However, clinical tumour staging is inaccurate pre-operatively; therefore, a template-based LND should be offered to all high-risk patients who are scheduled for RNU, especially given the low risk of major post-operative complications [201]. The templates for LND vary according to primary tumour location [193,202,203] and their use is likely to have a greater impact on survival than the number of removed LNs [204].

7.2.2. Kidney-sparing surgery

7.2.2.1. Distal ureterectomy

Distal ureterectomy, especially with adequate surgical margins based on frozen section analysis, followed by ureteroneocystostomy for high-risk UTUC located in the distal ureter only may be associated with similar oncological outcomes as RNU [149,150,205,206]. This procedure can be performed with concomitant LND. However, given the low level of evidence, this approach should only be used in highly selected cases where the benefits may be greater than the potential risks.

Ureterorenoscopy or segmental ureterectomy
For patients with high-risk UTUC but harbouring low-grade disease without any infiltrative features at imaging, tumour size and multifocality as well as hydronephrosis cannot be systematically considered as an indication for RNU [207,208]. Alternatively, the use of ureterorenoscopy with laser ablation or segmental ureterectomy can be proposed on a case-by-case basis if feasible.

7.2.2.2. Imperative indications

Ureterorenoscopy with laser ablation or segmental ureterectomy, can be considered on a case-by-case basis for patients with high-risk UTUC and imperative kidney-sparing indications. This includes situations such as solitary kidney, bilateral UTUC, even those harbouring high-grade disease and/or infiltrative features, but only in the presence of severe chronic kidney disease or any other comorbidity compromising the use of RNU. However, there is a greater risk of progression after kidney-sparing surgery for high- vs. low-risk UTUC with a direct impact on survival [149].

7.2.3. Peri-operative chemotherapy

7.2.3.1. Neoadjuvant treatments

7.2.3.1.1. Chemotherapy

The primary advantage of neoadjuvant chemotherapy (NAC) is the ability to give cisplatin-based regimens when patients still have maximal renal function. Several retrospective studies evaluating the role of NAC have shown evidence of pathological downstaging and complete response rates at RNU [209-213] with a direct impact on OS [214]. Furthermore, NAC has been shown to result in lower disease recurrence- and mortality rates compared to RNU alone, without compromising the use of definitive surgical treatment with a potential OS benefit [212,215-217].

No RCTs have been published yet but prospective data from phase II trials showed that NAC based on cisplatin combination therapy was associated with a 14-19% pathological complete response rate in high-grade and/or cT2-T4N0M0 UTUC [218,219]. In addition, final pathological stage was < ypT1 in more than 60% of included patients with acceptable toxicity profile. In a systematic review and meta-analysis comprising more than 800 patients, NAC has shown a pathologic partial response of 43% and a downstaging in 33% of patients, resulting in an OS and CSS survival benefit compared with RNU alone [220]. A further systematic review and meta-analysis of 14 trials, with 117 UTUC patients across 21 studies included 1,983 who received NAC. Of these 10% had pCR and 42% pathological downstaging but no survival outcome benefit was demonstrated [221]. However, it is important to note that the evidence in the meta-analysis is not conclusive, given the significant bias and heterogeneity of the available data and the lack of distinction between truly neoadjuvant and downstaging chemotherapy.

7.2.3.1.2. Immunotherapy

Only a small phase II study including 10 patients with high-risk UTUC evaluated the efficacy of pembrolizumab in the neoadjuvant setting [222]. However, no pathological response was observed and one treatment-related death was reported. Thus, there is currently no evidence to support the use of neoadjuvant immunotherapy for high-risk UTUC.

7.2.3.2. Adjuvant treatments

7.2.3.2.1. Bladder instillations

The rate of bladder recurrence after RNU for UTUC is 22–47% [190,223]. Two prospective randomised trials [224,225] and two meta-analyses [226,227] have demonstrated that a single post-operative dose of intravesical chemotherapy (mitomycin C, pirarubicin) 2–10 days after surgery reduces the risk of bladder tumour recurrence within the first years post-RNU in patients without a history of BC. Prior to instillation, a cystogram can be considered if there is concern about drug extravasation. All studies showed a very low risk of adverse events. Intravesical chemotherapy has also been safely given at the time of RNU prior to bladder cuff opening, removing the need for a post- operative cystogram, but with low level data for efficacy [228].

Based on current evidence it is unlikely that additional instillations beyond one peri-operative instillation of chemotherapy further substantially reduce the risk of intravesical recurrence [229]. Management is outlined in Figures 7.1 and 7.2. One low-level evidence study suggested that bladder irrigation might reduce the risk of bladder recurrence after RNU [230].

There are currently no data to support the use of bladder instillation of chemotherapy after kidney-sparing surgery as available RCTs included only patients who received RNU.

7.2.3.2.2. Systemic Chemotherapy

The POUT phase III multicentre prospective RCT (n = 261) evaluating the benefit of four cycles of adjuvant gemcitabine-platinum combination chemotherapy initiated within 90 days after RNU vs. surveillance has reported a significant improvement in disease-free survival (DFS) in patients with pT2–pT4, N (any) or positive (pT any, N1–3) M0 UTUC (3 year DFS 71% vs. 50%; 5 year DFS 63% vs. 46%; HR: 0.54; CI: 0.36-0.79; 3 & 5 year MFS 19% improvement HR: 0.55 CI: 0.0.36-0.77) [231]. Patients were stratified to gemcitabine/cisplatin or gemcitabine/carboplatin chemotherapy based on GFR alone with benefit seen irrespective of chemotherapy type. There was a non-significant trend towards improved OS (12% at 3 years) but as the study had met its primary endpoint of 3-year DFS, it closed early, leaving it underpowered for the secondary endpoint of OS. Updated analysis showed 5-year DFS of 62% vs. 45% (HR: 0.55, 95% CI: 0.38-0.80, p = 0.001) and mean restricted survival time was 18 months longer in the chemotherapy arm. Five-year OS was 66% vs. 57% with univariate HR: 0.68 (95% CI: 0.46, p = 0.49). Treatment effect was consistent across chemotherapy regimens (carboplatin or cisplatin) and disease stage [232]. The main potential limitation of using adjuvant chemotherapy is the concern that renal function may deteriorate after RNU precluding cisplatin use in patients who could benefit from this [233,234]. A review of perioperative predictors of decline in renal function after RNU showed 3-month GFR levels of around 50 mls/min [235]. With split dose and hydration cisplatin may be considered in patients with a GFR down to 45 mL/min. Table 2 outlines the eligibility criteria for platinum chemotherapy.

A potential nomogram to predict deterioration in post RNU renal function has been developed in 733 UTUC patients and validated in a retrospective cohort of 367 patients [236]. Multivariable predictors of post-operative eGFR decline included advanced age (OR: 0.18, 95% CI: 0.28-0.08), diabetes (OR: 2.38, 95% CI: 4.64 - 0.11), and hypertension (OR: 2.24, 95% CI: 4.16 - 0.32). Factors associated with favourable post-operative eGFR included larger tumour size (OR: 10.57, 95% CI: 7.4–13.74 for tumours > 5 cm vs. 2 cm) and pre-operative eGFR (OR: 0.44, 95% CI: 0.39 - 0.49). A composite nomogram predicted post-operative eGFR with good accuracy in both the discovery (80.5%) and validation (78.6%) cohorts. Limitations include exclusion of patients who received neoadjuvant chemotherapy.

In a retrospective study histological subtypes of UTUC exhibit different survival rates and adjuvant chemotherapy was only associated with an OS benefit in patients with pure UC [237]. However, whilst histological subtypes of UTUC exhibit different survival rates in retrospective studies, adjuvant chemotherapy should be considered whenever UC is the dominant pathology.

Table 2: Definitions of platinum-eligibility for systemic treatment of urothelial carcinoma [2]

* Carboplatin is not indicated for neoadjuvant treatment

7.2.3.2.3. Immunotherapy

In a phase III, multicentre, double-blind RCT involving patients with high-risk muscle-invasive UC who had undergone radical surgery (pT3, pT4a, or pN+), adjuvant nivolumab improved DFS compared to placebo in the intention-to-treat population (20.8 vs. 10.8 months) and among patients with a programmed death-ligand 1 (PD-L1) expression level of 1% or more [238]. The patient population predominantly consisted of BC patients post-radical cystectomy, with an additional smaller cohort of patients with UTUC post-RNU (approx 25%). The median recurrence-free survival outside the urothelial tract in the entire intention-to-treat population was 22.9 months for nivolumab and 13.7 months for placebo. Treatment-related adverse events > grade 3 occurred in 17.9% of the nivolumab group and 7.2% of the placebo group. On subgroup analysis, patients with UTUC included in this study did not seem to benefit from adjuvant nivolumab, which requires further follow-up and analysis. Nonetheless, the European Medicines Agency (EMA) approved nivolumab as monotherapy for the adjuvant treatment of patients with muscle-invasive UC and tumour cell PD-L1 expression > 1%, who are at high risk of recurrence after radical surgery and who decline or are unfit for adjuvant chemotherapy. [239]. A further study of 702 patients with urothelial cancer treated with either radical cystectomy or RNU, and with persistent high-risk features were randomised to receive either adjuvant pembrolizumab or observation [240]. The DFS was significantly longer with pembrolizumab 29.6 months vs. 14.2 months; however, the number of patients with UTUC (25% of overall population) in the study was small and on subgroup analyses did not seem to benefit from adjuvant pembrolizumab [240].

A network meta-analysis suggests superior oncological benefit for adjuvant platinum-based chemotherapy over immune checkpoint inhibitors in patients treated with radical surgery for UTUC [241].

7.2.3.2.4. Radiotherapy

Adjuvant radiation therapy has been suggested to control loco-regional disease after surgical removal. The data remains controversial and insufficient for conclusions [242-245]. Moreover, its added value to chemotherapy remains questionable [244].

7.2.4. Summary of evidence and recommendations for the management of high-risk non-metastatic UTUC

Figure 7.1: Proposed flowchart for the management of UTUC 

a: In patients with solitary kidney consider a more conservative approach.
b: In low-grade patients without invasive features consider a more conservative approach. 
CTU = computed tomography urography; RNU = radical nephroureterectomy; UTUC = upper urinary tract urothelial carcinoma.

Figure 7.2: Surgical treatment according to location and risk status 

a: In patients with solitary kidney consider a more conservative approach.
b: In low-grade patients without invasive features consider a more conservative approach.
1 = first treatment option; 2 = secondary treatment option.
*In case not amendable to endoscopic management.
LND = lymph node dissection; RNU = radical nephroureterectomy; URS = ureteroscopy; UTUC = upper urinary tract urothelial carcinoma.

7.3. Metastatic disease

7.3.1. Clinical loco-regional lymph node metastases

Resectable cN+ patients should be offered induction platinum-based chemotherapy. RNU with template-based LND can be discussed in a multidisciplinary team and with patients responding to initial systemic therapy. In patients whose cancer progress, second-line treatment can be offered, similar to distant metastatic disease [246,247]. Unresectable cN+ patients should be treated as distant metastatic patients [248].

7.3.2. Distant metastases

7.3.2.1. Systemic treatments - First-line setting

7.3.2.1.1. Enfortumab vedotin + pembrolizumab combination therapy

For more than 23 years, despite multiple attempts with new agents and/or combinations of treatments, platinum-based chemotherapy remained standard of care for previously untreated advanced or metastatic urothelial cancer. In October 2023, the landscape changed dramatically with the EV302 phase III randomised multi-centre study. This compared the combination of the nectin 4 directed antibody-drug conjugate enfortumab vedotin with the check point inhibitor pembrolizumab, (EV+P) with platinum-based combination chemotherapy (gemcitabine-cisplatin or gemcitabine -carboplatin. See table 2 for definition of cisplatin eligibility).

This study showed significant improvement in both PFS (HR: 0.45 [0.38-0.54]) and OS (HR: 0.47 [0.38-0.58]) with RR of 68% (vs. 44%) and CR 29%. Overall survival benefit was seen across subgroups regardless of cisplatin eligibility. The most common grade 3 or above TRAE of special interest included skin reactions (15.5%), peripheral neuropathy (6.8%) and hyperglycaemia (6.1%). The proportion of UTUC patients in this study was 25% and pre-planned subgroup analysis showed benefit irrespective of tumour location [249].

Sequencing of treatment after EV+Pembro is currently unclear and later line treatments will depend upon what agents the patient has previously received (Figure 7.3).

7.3.2.1.2. Patients ineligible for EV+Pembro and fit for cisplatin-based combination chemotherapy

Upper tract UC and urothelial BC both respond to systemic platinum-based chemotherapy. Eligibility to platinum-based chemotherapy in the metastatic setting is based on the same criteria outlined in Table 2. A retrospective analysis of three RCTs showed that primary tumour location in the lower- or upper urinary tract had no impact on progression-free survival (PFS) or OS in patients with locally-advanced or metastatic UC treated with platinum-based combination chemotherapy [250]. Therefore, cisplatin-containing combination chemotherapy is the standard treatment for advanced or metastatic UTUC ineligible for EV + Pembro [2]. A number of cisplatin-containing chemotherapy regimens have proven efficacy although gemcitabine and cisplatin are the most widely used. The use of cisplatin-based chemotherapy is widely considered in patients with eGFR > 45 mL/min [250].

The efficacy of immunotherapy using PD1 or PD-L1 inhibitors has been evaluated in the first-line setting for the treatment of cisplatin/carboplatin-fit patients with metastatic UC, including those with UTUC [251]. First-line immune checkpoint inhibitors or the combination of platinum-based chemotherapy with immune checkpoint inhibitors have not previously resulted in positive significant survival advantages and were thus not previously recommended [252-254]. These studies included both cisplatin and carboplatin combinations.

A phase III RCT in advanced/metastatic urothelial cancer has now shown an overall benefit from the addition of nivolumab to chemotherapy (gemcitabine-cisplatin). Median OS was improved (21.7 months vs. 18.9 months HR: 0.78 [0.63-0.96]) as well as median PFS (7.9 months vs. 7.6 months HR: 0.72 [0.59-0.88]). Objective RR were 57.6% compared with 43.1% for chemotherapy alone [255]. Although there is no sub-group analysis based on tumour position in this study, 12.6% of patients had UTUC.

7.3.2.1.3. Patients ineligible for Ev+Pembro and unfit for cisplatin-based combination chemotherapy

Carboplatin-based chemotherapy is recommended in patients unfit for cisplatin [2]. Carboplatin with gemcitabine is the preferred regimen [256], irrespective of PDL-1 status. In a recent critical re-analysis of RCTs comparing OS after cisplatin vs. carboplatin-based regimens in advanced UC, cisplatin conferred a minor OS benefit compared to carboplatin [257].

7.3.2.1.4. Maintenance therapy after first-line platinum-based chemotherapy

Maintenance avelumab is recommended in patients with complete/partial response or stable disease after 4–6 cycles of platinum-based chemotherapy, given in the first line setting only. Data from a phase III RCT showed that the use of avelumab maintenance therapy after four to six cycles of gemcitabine plus cisplatin or carboplatin (started within ten weeks of completion of first-line platinum-based chemotherapy) significantly prolonged OS as compared to best supportive care alone in those patients with advanced or metastatic UC who did not experience disease progression during, or responded to, first-line chemotherapy (HR: 0.69; 95% CI: 0.56–0.86) [258,259]. An increase in median OS from 14 to 21 months was observed with avelumab. Although no subgroup analysis based on tumour location was available in this study, almost 30% of the included patients had UTUC. Similarly, in a phase II study comprising 108 patients with metastatic UC achieving at least stable disease on first-line platinum-based chemotherapy, maintenance pembrolizumab improved PFS compared to placebo (5.4 vs. 3.0 months) [260].

7.3.2.1.5. Patients unfit for any combination therapy

Pembrolizumab or atezolizumab are alternative choices for patients who are PD-L1 positive and not eligible/ fit for platinum-based chemotherapy. In a single-arm phase II trial (n = 370) of cisplatin-ineligible UC, pembrolizumab monotherapy was associated with an objective response rate of 26% in 69 metastatic UTUC patients [261]. In the overall cohort, a PD-L1 expression of 10% was associated with a greater response rate to pembrolizumab. Treatment-related toxicity was in line with previous studies. In a single-arm phase II trial (n = 119) of cisplatin-ineligible UC, atezolizumab monotherapy was associated with an objective response rate of 39% in 33 (28%) metastatic UTUC patients [262]. Median OS in the overall cohort was 15.9 months and treatment-related toxicity was in line with previous studies [253].

7.3.2.2. Systemic treatments - later line setting

Subsequent treatments depend on the type of treatment given in the first line setting.

7.3.2.2.1. Platinum based chemotherapy

Platinum based chemotherapy should be the second line treatment of choice if not received in the first line setting. No data supports the use of maintenance avelumab outside of the first-line setting. In addition, patients in this category are likely to have already received a checkpoint inhibitor in the first-line setting, either in combination with EV or as monotherapy.

7.3.2.2.2. Immunotherapy

A phase III RCT including 542 patients who received prior platinum-based chemotherapy for advanced UC showed that pembrolizumab decreased the risk of death compared to second-line chemotherapy (the investigator’s choice of paclitaxel, docetaxel, or vinflunine); median OS: 10.3 months for pembrolizumab and 7.4 months for chemotherapy (HR: 0.73; 95% CI: 0.59–0.91) [263]. Responses were more frequent and durable for pembrolizumab compared to chemotherapy (21% vs. 11%). In the UTUC subgroup (n = 75/13.8%), the OS benefit seemed larger (50%).

The IMVigor211 trial explored atezolizumab in PD-L1-positive tumours in patients with tumours which relapsed after platinum-based chemotherapy; it failed to show a significant OS advantage of atezolizumab compared to second-line chemotherapy [264].

Other immunotherapies such as nivolumab [265], avelumab [266,267] and durvalumab [268] have shown objective response rates ranging from 17.8% [268] to 19.6% [265] and median OS ranging from 7.7 months to 18.2 months in patients with platinum-resistant metastatic UC. These results were obtained from single- arm phase I or II trials only and the number of UTUC patients included in these studies was only specified for avelumab (n = 7/15.9%) without any subgroup analysis based on primary tumour location [267].

The immunotherapy combination of nivolumab plus ipilimumab has shown significant anti-tumour activity with objective response rate up to 38% in a phase I/II multicentre trial including 78 patients with metastatic UC experiencing disease progression after platinum-based chemotherapy [269]. Although UTUC patients were included in this trial, no subgroup analysis was available. Other immunotherapy combinations may be effective in the second-line setting but data are currently limited [270].

7.3.2.2.3. Novel agents

Fibroblast growth factor receptors (FGFR) inhibition

Erdafitinib, a pan-FGFR tyrosine kinase inhibitor of FGFR1–4, was associated with a 40% radiological response rate according to the Response Evaluation Criteria in Solid Tumours (RECIST) in a phase II trial of 99 patients with locally-advanced or metastatic UC who progressed after first-line chemotherapy and harboured a FGFR DNA genomic alterations (FGFR2/3 fusions or FGFR3 mutations) [122]. This study included 23 UTUC patients with visceral metastases showing a 43% radiological response rate. The subsequent phase III Thor trial randomised 266 patients with advanced UC who had had similar mutations and had experienced disease progression after 1-2 lines of previous treatment, to treatment with either erdafitinib or investigators choice of chemotherapy (vinfunine or docetaxel). Significant improvements in median OS, (4.3 months; HR: 0.64; CI: 0.47-0.88), PFS 2.9 months (58; CI: 0.44-0.78) and a 36% risk reduction in death were observed; 33.5% of patient in this study had UTUC [271]. As the rate of activating alterations of FGFR3 is higher in UTUC than in bladder cancer [272], a potentially greater impact of FGR3 targeting agents is anticipated. UTUC patients should be tested for FGFR alterations (FGFR2/3 mutations or FGFR3 fusions) prior to erdafitinib treatment. Early testing for FGFR 2/3 alterations, mutations, and deletions should be considered for patients presenting with advanced/metastatic UTUC (Table 5.7).

Antibody drug conjugates (ADC)

A phase II study enrolled 89 patients (of whom 43% had UTUC) with cisplatin-unfit metastatic UC experiencing disease progression after therapy with PD-1 or PD-L1 inhibitors. All patients received the antibody-drug conjugate enfortumab vedotin. The objective radiological response rate (RECIST) was 52% of which 20% of patients achieved complete response [273]. In a phase III trial of enfortumab vedotin for the treatment of patients with locally-advanced or metastatic UC who had previously received platinum-containing chemotherapy and had disease progression during or after treatment with a PD-1 or PD-L1 inhibitor, enfortumab vedotin significantly prolonged survival as compared to standard chemotherapy (median OS 12.88 vs. 8.97 months) [274].

In an open-label phase II trial a total of 108 patients with metastatic UC who progressed after platinum-based chemotherapy and checkpoint inhibitors were treated with the antibody-drug conjugate sacituzumab govitecan. The objective radiological response rate was 27%, with median duration of response of 7.2 months, median PFS of 5.4 months and median OS of 10.9 months. However, the proportion of patients with UTUC was not mentioned in the publication [275].

A pre-planned subgroup analysis from the phase III RANGE trial assessed the impact on outcomes and safety of ramucirumab added to docetaxel after disease progression on both platinum-based chemotherapy and immune checkpoint inhibitors [276]. Median PFS was 3.15 months on ramucirumab/docetaxel vs. 2.73 months on placebo/docetaxel (HR: 0.786; 95% CI: 0.404–1.528, p = 0.4877). This trend for ramucirumab benefit occurred despite the ramucirumab arm having a higher percentage of patients with poorer prognosis. However, these findings need confirmation by further studies, as this analysis is limited by patient numbers and an imbalance in the treatment arms.

7.3.2.3. Surgery

7.3.2.3.1. Radical nephroureterectomy

Data regarding RNU in the metastatic setting are lacking with mainly retrospective observational studies [277-279].

Although evidence remains very limited, RNU may be associated with CSS [278,280,281] and OS benefit in selected patients, especially those fit enough to receive cisplatin-based chemotherapy [277,278]. It is noteworthy that these benefits may be limited to those patients with only one metastatic site [278]. Nonetheless, given the high risk of bias of the observational studies addressing RNU for metastatic UTUC, indications for RNU in this setting should mainly be reserved for palliative patients, aimed at controlling symptomatic disease [22,282].

7.3.2.3.2. Metastasectomy

There is no UTUC-specific study supporting the role of metastasectomy in patients with advanced disease. Reports suggesting that resection of metastatic lesions could be safe and oncologically beneficial in selected patients should be interpreted with caution [283-287]. In the absence of data from RCTs, patients should be evaluated on an individual basis and the decision to perform a metastasectomy (surgically) should be made following a shared decision-making process with the patient.

Figure 7.3 Flowchart for the management of metastatic upper tract urothelial carcinoma 

*In view of lack of subgroup analysis data for UTUC.
CPI=checkpoint inhibitor; EV = enfortumab vedotin; FGFR = fibroblast growth factor receptor; GFR = glomerular filtration rate; PS = performance status; PD-L1= programmed death-ligand 1; PD= programmed death.

7.3.3. Summary of evidence and recommendations for the treatment of metastatic UTUC

DNA = deoxyribonucleic acid; FGFR = fibroblast growth factor receptors; HD-MVAC = high-dose intensity methotrexate, vinblastine, adriamycin plus cisplatin; PD-L1 = programmed death ligand 1.