Editing Upper Urinary Tract Urothelial Cancer (section)

====== 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>'''
****<span style="color:#ff00ff">'''CheckMate 274 (adjuvant nivolumab)'''</span>
*****'''Population: 709 patients with high risk of recurrence after radical surgery for muscle-invasive urothelial carcinoma of the bladder, ureter, or renal pelvis, with or without neoadjuvant cisplatin-based therapy'''
******'''High risk defined as'''
*******'''Pathological stage pT3, pT4a, or pN+ and patient not eligible for or declined adjuvant cisplatin-based combination therapy for patients without previous neoadjuvant cisplatin-based chemotherapy'''
*******'''Pathological stage ypT2 to ypT4a or pyN+ for patients who received neoadjuvant cisplatin'''
******'''Enrollment of patients with upper tract urothelial carcinoma capped at approximately 20%'''
*****'''Randomized 1:1 to nivolumab''' (240 mg intravenously) '''or placebo''' every 2 weeks for up to 1 year
*****'''Outcomes:'''
******'''Primary: disease-free survival'''
*******Among all the patients (intention-to-treat population)
*******Among patients with a tumor programmed death ligand 1 (PD-L1) expression level of ≥1%
******Secondary: survival free from recurrence outside the urothelial tract, overall survival, and disease-specific survival
*****'''Results'''
******'''Median follow-up: ≈20 months'''
******'''Primary outcome: disease-free survival'''
*******'''Disease-free survival benefit: 10 months''' (21 months nivolumab vs. 11 months placebo)
*******Absolute disease-free survival benefit at 6 months:
*******All patients: 15% (75% adjuvant nivolumab vs. 60% placebo)
*******PD-L1 patients (40% of all patients): 18% (74% adjuvant nivolumab vs. 56% placebo)
*******'''In patients with upper tract urothelial carcinoma, hazard ratio in favour of placebo'''
******Secondary outcomes:
*******Distant metastasis-free survival improved with adjuvant nivolumab in both groups
*******Overall survival and disease-specific survival not reported
******Adverse events
*******Most common adverse events in nivolumab group: pruritis (23%), fatigue (17%), and diarrhea (17%)
*******Most common adverse events of grade 3 or higher in nivolumab group: elevated serum lipase (5%), elevated serum amylase (4%), diarrhea (1%), colitis (1%), and pneumonitis (1%)
*******3/351 (1%) treatment-related deaths in nivolumab group, 2 from pneumonitis, 1 from bowel perforation
*****[https://pubmed.ncbi.nlm.nih.gov/34077643/ Bajorin, Dean F., et al.] "Adjuvant nivolumab versus placebo in muscle-invasive urothelial carcinoma." ''New England Journal of Medicine'' 384.22 (2021): 2102-2114.
****'''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.'''