What systemic treatment would you recommend for a patient with a history of grade 5 urothelial carcinoma with perineural invasion, status post left nephroureterectomy, now presenting with paraaortic and lung metastases?

Systemic Treatment for Metastatic Upper Tract Urothelial Carcinoma

For this patient with metastatic upper tract urothelial carcinoma (paraaortic and lung metastases) following nephroureterectomy, first-line treatment should be cisplatin-based combination chemotherapy (gemcitabine plus cisplatin or HD-MVAC) if the patient is platinum-eligible, followed by maintenance avelumab if stable disease or better is achieved. 1

First-Line Treatment Selection

Platinum-Eligible Patients (Primary Recommendation)

• Cisplatin-containing combination chemotherapy with gemcitabine plus cisplatin (GC) or high-dose intensity methotrexate, vinblastine, adriamycin, and cisplatin (HD-MVAC) is the standard first-line treatment for metastatic urothelial carcinoma, including upper tract disease. 1

• Maintenance avelumab should be initiated in patients achieving stable disease or better after first-line platinum-based chemotherapy, as this provides significant survival benefit. 1

• Cisplatin eligibility requires adequate renal function, which is a critical consideration in this post-nephroureterectomy patient who has lost one renal unit. 2

Assessing Platinum Eligibility Post-Nephroureterectomy

This is a critical decision point that directly impacts treatment options:

• Only 37% of patients have preoperative eGFR ≥60 mL/min/1.73 m², which decreases to 16% after radical nephroureterectomy. 2

• For cisplatin eligibility using the threshold of ≥45 mL/min/1.73 m², 72% qualify preoperatively but only 52% postoperatively. 2

• Check current eGFR immediately - if ≥60 mL/min/1.73 m², the patient is clearly cisplatin-eligible; if 45-60 mL/min/1.73 m², cisplatin may still be considered; if <45 mL/min/1.73 m², carboplatin-based regimens should be used. 1

Carboplatin-Based Regimens (If Cisplatin-Ineligible)

• Use carboplatin plus gemcitabine combination if the patient is unfit for cisplatin but fit for carboplatin. 1

• This applies when renal function is inadequate for cisplatin (eGFR <45-60 mL/min/1.73 m²) or other contraindications exist (hearing loss, neuropathy, heart failure). 1

Alternative First-Line Options (If Platinum-Unfit)

• Consider pembrolizumab or atezolizumab monotherapy only in patients unfit for any platinum-based chemotherapy AND with high PD-L1 expression (CPS ≥10 for pembrolizumab in bladder cancer; definitions vary by agent). 1

• This is a weak recommendation and should only be used when platinum chemotherapy is truly contraindicated. 1

Emerging First-Line Option: Enfortumab Vedotin Plus Pembrolizumab

A paradigm shift is occurring in first-line treatment:

• The combination of enfortumab vedotin plus pembrolizumab (EV+P) demonstrated striking improvement in overall survival compared to chemotherapy followed by maintenance avelumab in 2024 trials. 3, 4

• Pembrolizumab, in combination with enfortumab vedotin, is FDA-approved for first-line treatment of locally advanced or metastatic urothelial cancer. 5

• This combination requires careful management of specific adverse events including skin reactions, peripheral neuropathy, and immune-related adverse events. 3

• Consider EV+P as first-line therapy, particularly if the patient has adequate support systems for managing toxicities and good performance status. 3, 4

Second-Line Treatment Options

If disease progresses on or after platinum-based chemotherapy:

• Offer pembrolizumab as second-line monotherapy - this is a strong recommendation for patients experiencing disease progression during or after platinum-based combination chemotherapy. 1

• Pembrolizumab is FDA-approved as a single agent for locally advanced or metastatic urothelial carcinoma with disease progression during or following platinum-containing chemotherapy. 5

Third-Line and Beyond

After progression on both platinum chemotherapy and immunotherapy:

• Offer enfortumab vedotin as monotherapy - this is strongly recommended and provides significant survival benefit compared to chemotherapy in this setting. 1

• Consider sacituzumab govitecan in clinical trials or off-label use - this antibody-drug conjugate shows promise in heavily pretreated patients. 1

• Test for FGFR2/3 genetic alterations and offer erdafitinib if alterations are present - this provides response rates of approximately 59% in patients progressing after immunotherapy and chemotherapy. 1

Upper Tract-Specific Considerations

Systemic therapy for advanced upper tract urothelial carcinoma follows bladder cancer recommendations:

• Most clinical decision-making is extrapolated from bladder cancer evidence, as upper tract disease represents only 5-10% of urothelial carcinomas. 1

• Systemic therapy for advanced upper tract disease should follow the same recommendations as urothelial bladder cancer. 1

• The aggressive nature of this patient's presentation (grade 5 with perineural invasion, now with paraaortic and lung metastases) warrants immediate systemic therapy without delay. 1

Critical Pitfalls to Avoid

• Do not delay treatment while waiting for molecular testing - initiate platinum-based chemotherapy immediately if eligible, and obtain FGFR testing for potential later-line therapy. 1

• Do not use carboplatin-based regimens as first choice if cisplatin is feasible - cisplatin-based regimens have superior efficacy. 1

• Do not omit maintenance avelumab if the patient achieves stable disease or better on first-line platinum chemotherapy - this significantly improves outcomes. 1

• Do not use immunotherapy monotherapy as first-line in platinum-eligible patients - this is only appropriate for platinum-ineligible patients with high PD-L1 expression. 1

• Do not assume adequate renal function post-nephroureterectomy - median eGFR decreases by 18.2% after radical nephroureterectomy, potentially affecting cisplatin eligibility. 2

Practical Treatment Algorithm

1. Assess renal function immediately (eGFR calculation) 2
2. If eGFR ≥60 mL/min/1.73 m² and good performance status: Consider EV+P first-line OR cisplatin-based chemotherapy (GC or HD-MVAC) followed by maintenance avelumab 1, 5, 3
3. If eGFR 45-60 mL/min/1.73 m²: Cisplatin may be considered with caution OR carboplatin plus gemcitabine 1
4. If eGFR <45 mL/min/1.73 m²: Carboplatin plus gemcitabine 1
5. If platinum-unfit with high PD-L1: Pembrolizumab or atezolizumab monotherapy 1
6. At progression on platinum: Pembrolizumab (if not already used) 1, 5
7. At progression on platinum + immunotherapy: Enfortumab vedotin OR erdafitinib (if FGFR2/3 altered) OR sacituzumab govitecan 1