Editing Upper Urinary Tract Urothelial Cancer (section)

==== Neoadjuvant/Adjuvant Therapy After Complete Excision====
=====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.[https://pubmed.ncbi.nlm.nih.gov/37096584/]</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.
***'''<span style="color:#ff00ff">ODMIT-C (2011)</span>'''
**** '''Population: 284 patients with no previous or concurrent history of bladder cancer undergoing nephroureterectomy for suspected UTUC'''
**** '''Randomized to a single postoperative intravesical dose of MMC''' (40 mg in 40 ml saline) '''at the time of urinary catheter removal''' '''vs. standard management'''
**** '''Results:'''
***** '''Risk of bladder tumour in first year reduced by 11%''' (27% MMC vs. 16% standard treatment)
**** [https://pubmed.ncbi.nlm.nih.gov/21684068/ O'Brien, Tim, et al.] "Prevention of bladder tumours after nephroureterectomy for primary upper urinary tract urothelial carcinoma: a prospective, multicentre, randomised clinical trial of a single postoperative intravesical dose of mitomycin C (the ODMIT-C Trial)." European urology 60.4 (2011): 703-710.
*** 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 Therapy=====

* '''Neoadjuvant''' 
** '''No randomized trials evaluating benefit of neoadjuvant therapy for UTUC.'''
** '''Chemotherapy'''
*** The use of agents for UTUC has been extrapolated from chemotherapy regimens used in bladder urothelial cancer
*** '''<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.[https://pubmed.ncbi.nlm.nih.gov/37096584/]</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.
****Phase II trial of 30 patients with high-grade UTUC found that 4 cycles of neoadjuvant methotrexate, vinblastine, doxorubicin and cisplatin was associated with a 14% pathological complete response rate.[https://pubmed.ncbi.nlm.nih.gov/31702432/]
**** 2020 meta-analysis of 14 studies for NAC in UTUC found that the pooled pathologic complete response rate (≤ypT0N0M0) was 11% and pathologic partial response rate (≤ypT1N0M0) was 43%.[https://pubmed.ncbi.nlm.nih.gov/32798146/]
***'''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.'''
**** A disadvantage of adjuvant chemotherapy is that many patients have baseline chronic kidney disease, which worsens after nephroureterectomy, rendering them ineligible to receive the full-dose cisplatinum-based chemotherapy
***'''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''' 
** '''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[https://pubmed.ncbi.nlm.nih.gov/37096584/]</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.'''
***** '''<span style="color:#ff00ff">POUT</span>'''
****** '''Population: 260 patients with histologically confirmed pT2-T4, N0-3, M0 or pTany, N+, MO UTUC'''
*******'''Pathological T stage: pT2 in 28%, pT3 in 66%, and pT4 in 6%'''
*******'''Nodal stage: N0 in 91%''', N1 in 6%, N2 in 3%, N3 in <1%
*******'''Site of tumour: renal pelvis in 35%, ureter in 34%, both renal pelvis and ureter in 30%''', and missing data in 1%
*******GFR: 30–49 in 36%, ≥50 in 64%
****** '''Randomized to 4 cycles of gemcitabine-cisplatin''' (gemcitabine-carboplatin if GFR 30-49ml/min) '''or surveillance with subsequent chemotherapy, if required'''
****** '''Primary outcome: disease-free survival'''
****** Secondary endpoints included metastasis-free survival, overall survival, toxicity & quality of life
****** '''Results'''
******* '''Trial closed early as data met early stopping rule for efficacy'''
******* Median follow-up: 30 months
******* '''Disease-free survival improved by 21% at 3 years''' (71% chemotherapy vs. 46% surveillance; HR 0.45)
******* '''Significantly improved metastasis-free survival; OS data not mature'''
******* Toxicity: neutropenia, thrombocytopenia, nausea, febrile neutropenia, vomiting; QOL worse initially with chemotherapy, similar by 6 monthsA 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'''
****** [https://pubmed.ncbi.nlm.nih.gov/32145825/ Birtle, Alison, et al.] "Adjuvant chemotherapy in upper tract urothelial carcinoma (the POUT trial): a phase 3, open-label, randomised controlled trial." The Lancet (2020).
***'''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+)[https://pubmed.ncbi.nlm.nih.gov/37096584/]</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:<span style="color:#ff0000">[https://pubmed.ncbi.nlm.nih.gov/37096584/]</span>'''
****#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.
***'''Radiation'''
**** Radical nephroureterectomy alone provides a high rate of local control; '''adjuvant radiation''' without chemotherapy for high-stage disease '''does not protect against a high rate of distant failure'''
**** Retrospective studies suggest that there may be a role for combined radiation-chemotherapy regimens in patients with advanced disease with adverse features