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

=== Surgical Removal ===

==== Indications ====

* '''Preferred'''
** '''Surgically eligible patients with HR UTUC'''

==== Approaches ====
#'''Radical nephroureterectomy with complete bladder cuff excision (BCE)''' 
#*'''RNU with complete bladder cuff excision and lymphadenectomy is the standard of care for patients with HR UTUC.'''
#'''Segmental ureterectomy'''
===== Radical nephroureterectomy =====

*'''Principles'''
*#'''Complete excision of ipsilateral upper tract urothelium''', including the intramural portion of the ureter and ureteral orifice with negative margins
*##Specimen should be removed en bloc whenever technically feasible
*#'''Avoidance of urinary spillage,''' such as by early low ligation of the ureter, to minimize the risk of seeding urothelial cancer outside the urinary tract.
*'''Approach'''
**Open, robotic, and laparoscopic approaches are suitable
***Minimally invasive approaches were associated with favorable perioperative outcomes including shorter length of stay and fewer complications, and, therefore, are favored for most patients when principles of RNU can be maintained
***Consider open surgical approaches for large, bulky UTUC with clinical evidence for direct invasion to adjacent structures
*'''Bladder cuff excision'''
**Worse local and metastatic recurrence rates with associated decreased CSS and OS for patients who did not receive complete BCE.
**Approach
***Extravesical or transvesical l (e.g., midline cystotomy)
***Open, minimally invasive or transurethral endoscopic techniques. 
****Transurethral endoscopic approaches are associated with higher recurrence rates in the bladder and may limit the ability to utilize post-NU intravesical therapies if the bladder is not fully closed
*'''Complication rates following RNU'''
**Range from 15% to 50% 
**'''30-day mortality risk of 1%'''

===== Ureterectomy =====

*'''Options'''
**'''<span style="color:#ff0000">Segmental ureterectomy with ureteroureterostomy</span>''' 
***'''<span style="color:#ff0000">Small, unifocal tumors (typically 1 cm or smaller) tumors isolated to a short segment of the proximal or mid-ureter requiring resection of ≤2 cm or less of ureteral length to allow for primary ureteroureterostomy.</span>''' 
****Longer sections of ureteral involvement and resection may require more complex reconstruction techniques when kidney sparing is desired.
**'''<span style="color:#ff0000">Distal ureterectomy with ureteral reimplant</span>'''
***'''<span style="color:#ff0000">Preferred treatment for surgically eligible patients with HR and unfavorable LR cancers endoscopically confirmed as confined to the lower ureter in a functional renal unit</span>'''
****Tumor ablation considered alternative options to the gold-standard of extirpative resection
*****Tumor ablation may yield less optimal results and require multiple additional procedures
***Most favorable candidates for distal ureterectomy are patients who
****Have ureteral tumors in the lower third of the ureter
****Sufficiently mobile bladder with capacity to facilitate reimplantation with or without reconfiguration of the bladder to facilitate a tension-free anastomosis (i.e., Boari flap or psoas hitch maneuver).
*'''Reasonable alternatives to RNU for well-selected patients'''
*Principles
*#'''Patient counseling''' to describe techniques, potential requirements for urinary reconstruction and associated complications including the potential impact on postoperative bladder function.
*#'''Preoperative endoscopic assessment''' to evaluate sites of involvement and proximal extent of disease.
*#'''Preoperative assessment of bladder capacity''' and function in cases where more extensive reconstruction such as a Boari flap are anticipated to permit a tension free ureterovesical anastomosis or the use of bowel segments.
*#'''Intraoperative pathologic assessment''' (i.e., frozen sections) of proximal and distal margins to ensure complete resection with negative margins.
*#Reasonable attempts to '''avoid of spillage of urine''' into the surgical field.
*#'''Watertight, tension free closure''' to facilitate functional healing and avoid urine leak (of urine potentially contaminated with malignant cells).

*'''When performing NU or distal ureterectomy, the entire distal ureter including the intramural ureteral tunnel and ureteral orifice should be excised, and the urinary tract should be closed in a watertight fashion.'''
**The resultant hiatus in the bladder in the location of the excised ureteral orifice with or without the bladder cuff can be closed formally in a watertight fashion in one or more layers
***A formal BCE with watertight closure of the bladder cuff should be performed to
***#Avoid urinary extravasation from the bladder
***#Facilitate more rapid catheter removal
***#Permit instillation of intravesical adjuvant chemotherapy in the perioperative setting
***Delayed closure by secondary intension in a decompressed bladder without formal bladder closure has also been described.

===== Lymph node dissection =====
* '''<span style="color:#ff0000">If HR UTUC, LND recommended</span>'''
** No RCTs to evaluate the effect of LND on oncologic outcomes in patients undergoing NU or SU
** Sufficient non-randomized evidence to suggest an oncologic benefit to LND at the time of NU for patients with “HR” stratification by guidelines
** '''Recommended minimal templates in non-metastatic disease'''
*** '''Tumors in the pyelocaliceal system: lymph nodes of the ipsilateral great vessel extending from the renal hilum to at least the inferior mesenteric artery.''' 
*** '''Tumors in the proximal 2/3 of the ureter: lymph nodes of the ipsilateral great vessel extending from the renal hilum to the aortic bifurcation.''' 
*** '''Tumors in the distal 1/3 of the ureter: ipsilateral pelvic LND to include at minimum the obturator and external iliac nodal packets.''' 
*** Internal and common iliac nodal packets may be removed in the appropriate clinical setting.
*** Limited data suggest cranial migration of lymph node metastases to the ipsilateral great vessels such that higher dissection may be considered in the appropriate clinical setting and per clinician judgement
* '''<span style="color:#ff0000">If LR UTUC, LND optional</span>'''
**Limited evidence exists to support a beneficial role for LND at time of NU or ureterectomy among patients with LR UTUC

==== 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.