Editing AUA: Upper Tract Urothelial Carcinoma (2023) (section)

==== Neoadjuvant/Adjuvant Chemotherapy and Immunotherapy ====

===== Adjuvant intravesical chemotherapy =====
*'''<span style="color:#ff0000">In patients undergoing RNU or SU (including distal ureterectomy) for UTUC, a single dose of perioperative intravesical chemotherapy should be administered in eligible patients to reduce the risk of bladder recurrence.</span>'''
**The exact timing of therapy has varied including instilling intravesical chemotherapy at the time of catheter removal (ODMIT-C trial), while other retrospective series reported instillation during surgery or up to 48 hours postoperatively.
**Little data to support one intravesical chemotherapeutic over another.
***Many use gemcitabine over mitomycin due to risks of chemical peritonitis with extravesical extravasation of MMC
===== Systemic chemotherapy =====

====== Neoadjuvant systemic chemotherapy ======
*'''<span style="color:#ff0000">Cisplatin-based neoadjuvant chemotherapy should be offered to patients undergoing RNU or ureterectomy with HR UTUC, particularly in those patients whose post-operative eGFR is expected to be <60 mL/min/1.73m2 or those with other medical comorbidities that would preclude platinum-based chemotherapy in the post-operative setting.</span>'''
** The strongly positive data from these phase II trials, the established high-level evidence seen in bladder cancer trials, the consistent findings from pooled meta-analytic data, and the compelling clinical challenges imposed by post-RNU renal function on cis-platinum eligibility support the standard use of NAC regimens for HR UTUC.
* '''In the neoadjuvant setting, dosing regimens may be better tolerated, allowing more courses to be completed, and permitting patients to proceed to appropriate surgical intervention.'''
* '''Alternatives to cisplatin-based chemotherapy''' (i.e., immune checkpoint inhibitors, carboplatin, antibody drug conjugates, targeted FGFR therapies) '''are not recommended in the neoadjuvant setting''' (prior RNU or ureterectomy) outside of clinical trials

====== Adjuvant systemic chemotherapy ======
*'''<span style="color:#ff0000">Platinum-based adjuvant chemotherapy should be offered to patients with advanced pathological stage (pT2–T4 pN0–N3 M0 or pTany N1–3 M0) UTUC after RNU or ureterectomy who have not received neoadjuvant platinum-based therapy</span>'''
** '''Adjuvant platinum-based chemotherapy for select patients with UTUC post-RNU is a standard based on results from the randomized phase III POUT trial.'''
*** Subjects in the adjuvant chemotherapy arm had improved DFS and  lower risk of metastases or death, compared with those on observation.
*** A subgroup analysis demonstrated that outcomes for patients with lymph node involvement and those treated with carboplatin chemotherapy were worse than those without positive nodes or treated with cisplatin chemotherapy
**** '''Carboplatin remains a reasonable choice for HR cisplatin-ineligible patients post-RNU if NAC was not given'''

===== Adjuvant immunotherapy =====

* '''<span style="color:#ff0000">Adjuvant nivolumab therapy may be offered to patients who received neoadjuvant platinum-based chemotherapy (ypT2–T4 or ypN+) or who are ineligible for or refuse perioperative cisplatin (pT3, pT4a, or pN+)</span>'''
** CheckMate 274 evaluated adjuvant nivolumab following surgery in patients with HR non-metastatic urothelial carcinoma
*** Majority of patients underwent radical cystectomy for bladder primaries, 20% of patients underwent surgery for UTUC
*** Inclusion criteria for both studies were patients with HR urothelial cancer defined as pT3, pT4a, or pN+ for patients who had not received neoadjuvant cisplatin-based chemotherapy and ypT2 to ypT4a or ypN+ for patients who had received neoadjuvant cisplatin
*** Adjuvant nivolumab approved for UTUC and urothelial carcinoma of the bladder in patients with advanced disease identified from post-surgical pathology findings
** Adjuvant platinum-chemotherapy over adjuvant nivolumab is recommended for eligible patients who did not receive NAC. Scenarios for use of adjuvant nivolumab include: 
**# Patients with contraindications to platinum-based chemotherapy (e.g., poor renal function, performance status, sensorineural hearing loss, neuropathy or congestive heart failure, allergy)
**# Patients with HR pathology after NAC
**# Patients who refuse standard forms of adjuvant chemotherapy after appropriate counseling.