Editing Upper Urinary Tract Urothelial Cancer (section)

=== Non-metastatic disease ===

==== Options (4) ====
{| class="wikitable" style="width: 80%; margin: 0 auto;"
|-
| style="width: 40%;" | '''<span style="color:#ff0000">Nephron-sparing (3)</span>'''
| style="width: 40%;" | '''<span style="color:#ff0000">Non Nephron-sparing (1)</span>'''

|-
|
#'''<span style="color:#ff0000">Endoscopic Ablation/Resection</span>'''
## Ureteroscopic
## Percutaneous
# '''<span style="color:#ff0000">Intraluminal Therapy</span>'''
# '''<span style="color:#ff0000">Segmental Ureterectomy</span>'''
|
#'''<span style="color:#ff0000">Radical nephroureterectomy with bladder cuff excision</span>'''
|}
* Can also be classified as surgical removal (radical nephroureterectomy or segmental ureterectomy) vs. non-surgical removal (endoscopic ablation/resection or intraluminal therapy)
*'''Nephron-sparing approaches are associated with high risk of local recurrence'''; '''patients need to be followed vigilantly for disease progression.'''
=====Endoscopic Ablation/Resection=====

* '''Advantages'''
*# '''Minimally-invasive'''
*# '''Preserves renal function'''
* '''Disadvantages'''
*# '''High risk of recurrence'''
*# '''Risk of disease progression remains'''
*#* '''Due to the suboptimal performance of imaging and biopsy for risk stratification and tumour biology'''

====== Technical considerations ======
*'''Approach'''
** '''Retrograde (ureteroscopic) vs. antegrade (percutaneous)'''
*** '''Choice depends largely on the tumor location and size'''
**** '''Retrograde preferred when tumor size, number, and access allow complete tumor ablation.'''
**** '''Percutaneous antegrade tumor ablation preferred for (3):'''
****#'''Larger tumors'''
****#'''Tumor difficult to access in a retrograde fashion'''
****#'''Patients who have undergone prior radical cystectomy or urinary diversion'''
**** In cases with multifocal involvement, combined antegrade and retrograde approaches can be considered
** '''Retrograde approach'''
*** '''Advantages (2)''':
***# '''Lower morbidity than percutaneous and open surgical counterparts'''
***# '''Maintenance of a closed system'''
***#* '''Non-urothelial surfaces are not exposed to the possibility of tumor seeding'''
*** '''Disadvantages (2):'''
***# '''Smaller instruments required'''
***#* '''Smaller endoscopes have a smaller field of view and working channel which limits the size of tumor that can be approached in a retrograde fashion. These small instruments limit the accuracy of biopsies, especially with regard to staging'''
***# '''Some portions of the upper urinary tract, such as the lower pole calyces, cannot be reliably reached with working instruments.'''
*** '''Technique'''
**** Without ureteroscopic resectoscope
*****Debulk tumor by use of either biopsy forceps or a flat wire basket engaged adjacent to the tumor. 
******This technique is especially useful for low-grade papillary tumor on a narrow stalk. 
*****Treat tumor base with either electrocautery or laser energy sources. 
*****Send specimen for pathologic evaluation.
**** With ureteroscopic resectoscope
*****Use resectoscope to remove the tumor. 
******Only the intraluminal tumor is resected, and no attempt is made to resect deep (beyond the lamina propria).
**** A ureteral stent is placed for a variable duration to aid with the healing process.
** '''Antegrade approach'''
*** '''Advantages (4):'''
***# '''Ability to use larger instruments that can remove a large volume of tumor in any portion of the renal collecting system'''
***# '''Improved tumour staging and grading because deeper biopsy specimens are obtained'''
***# '''May avoid the limitations of flexible ureteroscopy, especially in complicated calyceal systems or areas difficult to access, such as the lower pole calyx or the upper urinary tract of patients with urinary diversion.'''
***# '''The established nephrostomy tract can be maintained for immediate postoperative nephroscopy and administration of topical adjuvant therapy'''
*** '''Disadvantages (4):'''
***# '''Increased morbidity compared with ureteroscopy'''
***# '''Risk of nephrostomy tract insertion'''
***# '''Procedure usually requires inpatient admission'''
***# '''Potential for tumor seeding outside the urinary tract; tract seeding is a possibility but appears to be an uncommon event'''
*** '''Technique'''
**** '''A nephrostomy tube is left in place.''' 
*****This access can be used for second-look follow-up nephroscopy to ensure complete tumor removal. 
****Follow-up (second-look) nephroscopy is performed 4-14 days later to allow adequate healing. 
*****The tumor resection site is identified, and any residual tumor is removed.
**** Complications from percutaneous management of tumors are similar to those for benign renal processes and include bleeding, systemic absorption of hypo-osmotic irrigation (with monopolar resection), perforation of the collecting system, and secondary ureteropelvic junction obstruction.
*'''Tumor size[https://pubmed.ncbi.nlm.nih.gov/37096584/]'''
** '''Tumors < 1.5 cm in size may be optimal for endoscopic ablation given a lower risk of invasive disease.'''
*** Tumors ≥ 1.5 cm in size are associated with a > 80% risk of invasive disease
***'''Larger tumors (≥ 1.5 cm) may be considered for ablation based on the provider’s experience and assessment of the need for kidney sparing surgery.'''
*Energy source[https://pubmed.ncbi.nlm.nih.gov/37096584/]
**Can be performed with laser or electrocautery
***Electrocautery is delivered through a small Bugbee electrode (2 or 3 Fr)
****However, the variable depth of penetration can make its use in the ureter dangerous, and circumferential fulguration should be avoided because of the high risk of stricture formation.
***Thulium, holmium (Ho:YAG), and Neodymium (Nd:YAG) are laser energies that have been used
* Chemoablation[https://pubmed.ncbi.nlm.nih.gov/37096584/]
**May be employed either through retrograde ureteral catheter instillation or percutaneous access with fluoroscopic imaging guidance
*Ureteral access sheath[https://pubmed.ncbi.nlm.nih.gov/37096584/]
**Prior to placement of any ureteral access sheath, the entire ureter should be directly visualized in order to avoid missing any luminal neoplasms, especially in the distal ureter
** Advantages (3):
**#Allows for repeated scope passage up and down the ureter for sampling
**#Means of fluid egress from the upper tract to avoid excess pelvicalyceal hydrostatic pressure from irrigation solutions
**#Lower rate of intravesical recurrence (based on observational study)

====== Outcomes ======
* '''<span style="color:#ff00ff">Systematic review of endoscopic management of UTUC (2012)</span>'''
** Results:
*** Included 34 studies, 22 on URS and 12 on percutaneous resection
**** All were case series (level of evidence 4), or non-randomized comparative studies (level of evidence 3b)
*** Mean sample size
**** URS: 33
**** PCN: 24
**** 3 institutions for URS and 1 for PCN, have published outcomes on cohorts of ≥ 40 patients with > 50 months follow-up, limiting generalizability
*** Estimated 5-yr:
**** Recurrence-free survival: 13 – 54%
**** Renal preservation: 85%
**** Cancer-specific survival: 49-89%
**** OS 57-75%
**** Recurrence-free and cancer-specific survival outcomes worsened with increasing grade
*** [https://pubmed.ncbi.nlm.nih.gov/22471401/ Cutress, Mark L., et al. "Ureteroscopic and percutaneous management of upper tract urothelial carcinoma (UTUC): systematic review." ''BJU international'' 110.5 (2012): 614-628.]
* '''Given high risk of recurrence with endoscopic management, patients should be informed of the need for early second-look and stringent surveillance.'''

======Adjuvant therapy======

* Options (2):'''
*# Intraluminal/instillation (chemo- or immunotherapy) therapy (see below)
*# Brachytherapy of the nephrostomy tract through iridium wire or delivery system

======Repeat Endoscopic Evaluation[https://pubmed.ncbi.nlm.nih.gov/37096584/]======
*'''<span style="color:#ff0000">Should be performed within 3 months</span>'''
**Proclivity of UTUC to recur and for residual disease to remain after the first ablation
**A 30-day window on either side of this endpoint (i.e., 30 to 90 days) is justified to allow timely identification of recurrences and may be dictated by aspects such as tumor size, visualization, access, treatment efficacy, etc., as clinically indicated
**'''<span style="color:#ff0000">If residual disease identified, repeat endoscopic assessment should occur within 3-month intervals until no evidence of upper tract disease is identified.</span>'''
*'''In patients with LR UTUC with evidence of risk group progression (tumor size, focality, or grade) or when tumor ablation is not feasible,''' further endoscopic-assisted attempts are not recommended. '''surgical resection of all involved sites either by RNU or segmental resection of the ureter should be offered.'''
=====Intraluminal Therapy=====

====== Indications (3): ======
# '''Adjuvant therapy after endoscopic or organ-sparing therapy'''
#'''Primary treatment for CIS (see Special Scenarios)'''
# '''Primary treatment of low-grade UTUC (UGN-101)'''

====== Adjuvant therapy ======
*'''Pelvicalyceal or intravesical chemotherapy following ablation of UTUC tumors[https://pubmed.ncbi.nlm.nih.gov/37096584/]'''
**Principle of an immediate instillation of intravesical or pyelocaliceal (upper tract) chemotherapy at the time of endoscopic tumor ablation for UTUC is undertaken by extrapolation of the data supporting immediate instillation of intravesical chemotherapy at the time of transurethral resection of a bladder tumor
**Options: thiotepa, mitomycin
**'''Indications'''
*** '''Considered optional'''
** Technique
***Prior to administration, must confirm that there is no perforation of the bladder or upper tract
***Approaches (3)
***#Antegrade perfusion by nephrostomy tube
***#Retrograde perfusion via ureteral catheter
***#Bladder instillation by transurethral catheter with reflux via a double J ureteral stent.
***#*In the third scenario, a cystogram and demonstration of adequate reflux of contrast into the pyelocaliceal system is recommended.
*'''Immunotherapy'''
**'''Pelvicalyceal BCG[https://pubmed.ncbi.nlm.nih.gov/37096584/]'''
***'''Indications'''
****'''May be offered to patients with HR favorable UTUC after complete tumor ablation or patients with upper tract carcinoma in situ (CIS).'''
****'''Imperative indications'''
****#'''Solitary kidney status'''
****# '''Bilateral UTUC'''
****#'''Risk of progression to end-stage renal disease'''
***Consists of a 6-week induction course of BCG
* '''Outcomes'''
**'''<span style="color:#ff00ff">Systematic review and meta-analysis (2019)</span>'''
*** Inclusion criteria: studies evaluating patients with upper tract urothelial carcinoma receiving instillation treatment as adjuvant/curative therapy for pTa/pT1 and CIS, respectively.
*** Studies with ≥10 participants included in quantitative analyses
*** Results
**** Included 212 patients from 12 studies of patients that underwent endoscopic laser ablation and instillation therapy for Ta/T1 UTUC
**** Recurrence-free survival: 40%
***** Similar to recurrence-free survival with observation after nephron-sparing surgery
**** Cancer-specific survival: 94%
**** Overall survival: 71%
**** No difference in survival based on approach (antegrade, retrograde, or combined) or drug (MMC vs. BCG)
*** [https://pubmed.ncbi.nlm.nih.gov/30846387/ Foerster, Beat, et al. "Endocavitary treatment for upper tract urothelial carcinoma: a meta-analysis of the current literature." ''Urologic Oncology: Seminars and Original Investigations''. Vol. 37. No. 7. Elsevier, 2019.]
* '''Adverse events'''
**'''Most common complication of intraluminal/instillation therapy is bacterial sepsis'''

====== <span style="color:#ff0000">Primary treatment for low-grade UTUC</span> ======
*Effectiveness of intraluminal therapy has been limited by inadequate exposure to urothelium from fluid preparations due to rapid drainage from (2)
**No storage capacity of UTUC (unlike bladder)
**Ureteral and pelvic peristalsis
*Potential solution is to use reverse thermosensitive polymers, which are liquid at room temperature and convert to a gel at body temperature, resulting in increased dwell time
*'''<span style="color:#ff0000">UGN-101</span>'''
**'''UGN-101 = MMC + reverse thermosensitive polymer'''
***Also known as Mitogel, Jelmyto
**'''<span style="color:#ff00ff">OLYMPUS (Lancet Oncology 2020</span>''')
*** Objective: evaluate the safety and activity of UGN-101 to treat primary and recurrent low-grade UTUC.
*** '''Design: open-label, single-arm, phase 3 trial'''
*** '''Population: 71 patients with primary or recurrent biopsy-proven, low-grade UTUC (involving the renal pelvis or calyces) and ≥1 low-grade lesion above the ureteropelvic junction, measuring 5–15 mm.'''
**** Lesions >15 mm were eligible for endoscopic downsizing before the initiation of treatment.
*** Treatment: 6 once-weekly treatments of UGN-101
*** '''Primary outcome: complete response,''' defined as
**** Negative endoscopic examination AND
**** Negative cytology at the primary disease evaluation AND
**** Negative for-cause biopsy when done
*** '''Results:'''
**** '''Primary outcome:'''
***** '''≈60% complete response at 3 months'''
****** Among those with complete response, ≈60% maintained complete response at 12 months[https://pubmed.ncbi.nlm.nih.gov/34915741/]
**** '''Adverse events'''
***** Common; 94% had any adverse event
***** 37% had ≥1 serious adverse event
****** '''44% ureteric stenosis[https://pubmed.ncbi.nlm.nih.gov/34915741/]'''
****** 20% renal dysfunction
*** [https://pubmed.ncbi.nlm.nih.gov/32631491/ Kleinmann, Nir, et al.] "Primary chemoablation of low-grade upper tract urothelial carcinoma using UGN-101, a mitomycin-containing reverse thermal gel (OLYMPUS): an open-label, single-arm, phase 3 trial." ''The lancet oncology'' 21.6 (2020): 776-785.
*'''Technique'''
**'''Approaches:'''
***'''Antegrade via percutaneous nephrostomy'''
*** '''Retrograde through a single J open-ended ureteric stent'''
**** '''Suboptimal because the drug often does not reach the renal pelvis'''
*** Both the antegrade and retrograde approach can be dangerous due to possible ureteric obstruction and consecutive pyelovenous influx during instillation/perfusion.
=====Segmental Ureterectomy=====
*'''Reasonable alternative to RNU for well-selected patients'''

====== 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).

====== 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).

====== Outcomes ======
* '''<span style="color:#ff00ff">Systematic review and meta-analysis comparing segmental resection to radical nephroureterectomy (2020)</span>'''
** Results:
*** Included 18 studies comprising 4797 patients, of which 1313 underwent segmental resection
*** High risk of bias across all domains analysed, limiting interpretation of comparisons
*** 5-yr:
**** Recurrence-free survival: significantly worse with segmental resection
**** Cancer-specific survival: no significant difference
**** OS: no significant difference
*** Veccia, Alessandro, et al."Segmental ureterectomy for upper tract urothelial carcinoma: a systematic review and meta-analysis of comparative studies." ''Clinical genitourinary cancer'' 18.1 (2020): e10-e20.
* Segmental ureterectomy of the proximal two-thirds of ureter is associated with higher failure rates than for the distal ureter.

====== Technique ======
* Risk of wound implantation by tumor is low after open segmental ureterectomy if simple precautions are followed to minimize spillage
*See Segmental Ureterectomy Chapter Notes for technical aspects
*'''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.
=====Radical nephroureterectomy with bladder cuff excision=====

====== Principles[https://pubmed.ncbi.nlm.nih.gov/37096584/] ======
#'''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.

====== Outcomes ======
*Largely dependent on clinicopathologic characteristics.
*'''<span style="color:#ff00ff">Systematic review and meta-analysis comparing nephron-sparing approach to radical nephroureterectomy (2016)</span>'''
** Primary outcome: cancer-specific survival
** Results
*** Included 22 studies published between 1999 and 2015
**** No RCTs comparing nephron-sparing approach and nephroureterectomy
*** High risk of bias across all domains analysed, limiting interpretation of comparisons
*** Segemental ureterectomy vs. RNU (10 studies): no significant difference in cancer-specific survival
*** Endoscopic vs. RNU
**** URS vs. RNU (5 studies): no significant difference in cancer-specific survival
***** Grade-based subgroup analyses found decreased cancer-specific survival in patients undergoing URS for high-grade disease
**** Percutaneous resection vs. RNU (2 studies): conflicting findings
** Seisen, Thomas, et al."Oncologic outcomes of kidney-sparing surgery versus radical nephroureterectomy for upper tract urothelial carcinoma: a systematic review by the EAU non-muscle invasive bladder cancer guidelines panel." ''European urology'' 70.6 (2016): 1052-1068.

====== Technique ======
*See Nephroureterectomy Chapter Notes for technical aspects
*'''Approach[https://pubmed.ncbi.nlm.nih.gov/37096584/]'''
**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[https://pubmed.ncbi.nlm.nih.gov/37096584/]'''
**Worse local and metastatic recurrence rates with associated decreased CSS and OS for patients who did not receive complete BCE.
** Approach
***Extravesical or transvesical (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

====== Adverse events ======
*Range from 15% to 50%
* '''30-day mortality risk of 1%'''

====Treatment Selection====

* '''Based on risk stratification (see above)'''

=====UrologySchool.com Summary=====
'''AUA'''
*'''<span style="color:#ff0000">If low-risk</span>'''
**'''<span style="color:#ff0000">Favorable</span>'''
***'''<span style="color:#ff0000">Tumor ablation (preferred, when technically feasible)</span>'''
****Observational studies suggest similar cancer-specific survival, similar complication rates, and improved renal function outcomes with endoscopic ablation, compared to nephroureterectomy
**'''<span style="color:#ff0000">Unfavorable</span>'''
***'''<span style="color:#ff0000">Tumor ablation (optional for patients with low-volume tumors or cannot undergo RNU)</span>'''
***'''<span style="color:#ff0000">Surgical removal (radical nephroureterectomy or segmental ureterectomy)</span>'''
**'''<span style="color:#ff0000">If low-risk and complete endoscopic ablation not feasible, chemoablation (in-situ tissue destruction) with mitomycin containing reverse thermal gel can be a treatment alternative</span>'''
*'''<span style="color:#ff0000">If high-risk</span>'''
** '''<span style="color:#ff0000">RNU with complete bladder cuff excision and lymphadenectomy is the standard of care for patients with HR UTUC.</span>'''
**'''<span style="color:#ff0000">Favorable</span>'''
***'''<span style="color:#ff0000">Surgical removal (preferred)</span>'''
***'''<span style="color:#ff0000">Tumor ablation (optional for patients with low-volume tumors or cannot undergo RNU)</span>'''
****'''<span style="color:#ff0000">Select patients who have low-volume tumors or cannot undergo RNU</span>'''
**'''<span style="color:#ff0000">Unfavorable</span>'''
***'''<span style="color:#ff0000">Surgical removal (preferred)</span>'''
**'''<span style="color:#ff0000">For surgically eligible patients with HR and unfavorable LR cancers endoscopically confirmed as confined to the lower ureter in a functional renal unit, distal ureterectomy with ureteral reimplant is the preferred treatment</span>''' 
==== Patient counseling[https://pubmed.ncbi.nlm.nih.gov/37096584/] ====
*'''<span style="color:#ff0000">Discuss and facilitate smoking cessation, if applicable,</span> with patients at the time of diagnosis and treatment.'''
** Risk factors such as smoking are associated with advanced disease stage, recurrence and worse cancer-specific mortality among patients with UTUC, with the highest risk among current smokers.
*'''<span style="color:#ff0000">Provide patients with a description of the short- and long-term risks associated with recommended diagnostic and therapeutic options, including</span>'''
*#'''<span style="color:#ff0000">Need for endoscopic follow-up</span>'''
*#*Urothelial recurrences are common in the management of UTUC, regardless of approach, and mandate long-term surveillance for which patients must be prepared – including the potential need for additional treatments.
*# '''<span style="color:#ff0000">Risks of treatment (3)</span>'''
*##'''<span style="color:#ff0000">Risk of clinically significant strictures with endoscopic management</span>'''
*##*Ablative options can provide local control including durable long-term kidney sparing outcomes but incur additional endoscopic surveillance requirements and associated risks such as stricture and infection
*##*Use of chemoablative treatment with the reverse thermo-hydrogel preparation of mitomycin for pyelocaliceal instillation for LG tumors carries an FDA label warning for ureteral obstruction (>44%), bone marrow suppression, and embryo-fetal toxicity.
*##'''<span style="color:#ff0000">Risk of post-nephroureterectomy CKD or dialysis</span>'''
*##*'''Risk factors for post-operative development of CKD or progression of pre-existing CKD (8):'''
*##*#'''Older age'''
*##*#'''Diabetes mellitus'''
*##*#'''Hypertension'''
*##*#'''Male sex'''
*##*#'''Obesity'''
*##*#'''Tobacco use'''
*##*#'''Larger tumor size'''
*##*#'''Post-operative acute kidney injury.'''
*##*'''Perioperative nephrology consultation can be considered, particularly in patients with pre-existing kidney disease.'''
*##**'''<span style="color:#ff0000">Indications for referral to nephrology (4):</span>'''
*##**# '''<span style="color:#ff0000">eGFR < 45 mL/min/1.73m2</span>'''
*##**#'''<span style="color:#ff0000">Confirmed proteinuria</span>'''
*##**#'''<span style="color:#ff0000">Diabetics with preexisting CKD</span>'''
*##**#'''<span style="color:#ff0000">If eGFR is expected to be < 30 mL/min/1.73m2 after intervention.</span>''' 
*##*In patients with pre-existing CKD or a solitary kidney, attempts to preserve renal function can be made, if oncologically feasible and appropriate, with segmental or endoscopic organ-sparing approaches which preferentially are associated with improved postoperative renal function.
*##*In patients with sufficiently poor CKD in which NU could precipitate ESRD, a post operative plan for dialysis in conjunction with nephrology colleagues should be in place preoperatively including plans for dialysis access. Referral to nephrology for detailed evaluation and recommendations for perioperative management is warranted in such cases
*##'''<span style="color:#ff0000">Side effects from neoadjuvant and adjuvant therapies.</span>''' 
====Lymph Node Dissection====

* No RCTs to evaluate the effect of LND on oncologic outcomes in patients undergoing NU or SU
* '''<span style="color:#ff0000">Indications</span>'''
** '''AUA'''
*** '''<span style="color:#ff0000">Recommended (1): HR UTUC</span>'''
**** Sufficient non-randomized evidence to suggest an oncologic benefit to LND at the time of NU for patients with “HR” stratification by guidelines
*** '''<span style="color:#ff0000">Optional (1): LR UTUC</span>'''
**** Limited evidence exists to support a beneficial role for LND at time of NU or ureterectomy among patients with LR UTUC
*'''Template based on tumor collection'''
**'''Pyelocaliceal system: lymph nodes of the ipsilateral great vessel extending from the renal hilum to at least the inferior mesenteric artery.''' 
**'''Proximal 2/3 of the ureter: lymph nodes of the ipsilateral great vessel extending from the renal hilum to the aortic bifurcation.'''
**'''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

==== 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
====Special scenarios====

===== CIS of the Upper Urinary Tracts =====
* '''In most cases, the diagnosis is one of exclusion wherein there is a persistent positive selective cytology in the absence of any ureteroscopic or radiographic findings.'''
** The diagnosis of CIS of the upper urinary tracts difficult because of the inability to evaluate the urothelium of the upper tracts with adequate tissue samples
* '''Management'''
** '''Not well established'''
** '''<span style="color:#ff0000">Current approaches for presumed upper tract CIS include topical immunotherapy or chemotherapy'''
*** '''Most experience is from use of BCG via a nephrostomy tube for primary treatment of CIS.'''
**** '''<span style="color:#ff00ff">Systematic review and meta-analysis evaluating intraluminal therapy for UTUC (2019)</span>'''
***** Inclusion criteria: studies evaluating patients with upper tract urothelial carcinoma receiving instillation treatment as adjuvant/curative therapy for pTa/pT1 and CIS, respectively.
***** Studies with ≥10 participants included in quantitative analyses
***** Results
****** Included 226 patients from 15 studies of patients that underwent BCG instillation for CIS
****** Recurrence-free survival: 84%
****** Cancer-specific survival: 34%
****** Overall survival: 16%
****** No difference in survival based on approach (antegrade, retrograde, or combined) or drug (MMC vs. BCG)
***** Foerster, Beat, et al. "Endocavitary treatment for upper tract urothelial carcinoma: a meta-analysis of the current literature." ''Urologic Oncology: Seminars and Original Investigations''. Vol. 37. No. 7. Elsevier, 2019.
*** Historically, '''<span style="color:#ff0000">radical nephroureterectomy</span>''' was performed for a unilateral cytologic abnormality of the upper tract to eliminate presumed CIS. This practice '''<span style="color:#ff0000">is not recommended</span>''' in the absence of any histologic, radiographic, or endoscopic finding '''owing to the limitations of cytology alone with false-positive results and the high risk for bilateral disease in the future'''
*** '''Observation is also not appropriate without further evaluation given the repeated abnormal cytologies.'''
* Management of CIS of ureteral margins during radical cystectomy is controversial

===== CIS limited to the region within the ureteral orifice =====
*Topical therapies such as BCG along with refluxing ureteral stenting that has been used for in cases of CIS near the ureterovesical junction or transurethral resection of the transmural portion of the ureter for very distal tumors, as an extension of bladder resection procedures, when tumor is limited to the region inside the ureteral orifice and not beyond the bladder wall, thus anatomically managed as bladder cancer

===== Watchful waiting or surveillance =====
*May be offered to select patients with UTUC with
**Significant comorbidities/competing risks of mortality
** Significant risk of End-Stage Renal Disease (ESRD) with any intervention resulting in dialysis.
*Discussion of treatment related risks including perioperative mortality may lead to a shared decision to proceed with active surveillance (whereby periodic assessments such as imaging or limited endoscopic assessment are performed) or watchful waiting/expectant management, where interventions are limited to palliation or awaiting symptomatic progression – especially in those with very limited life expectancy.
**In such cases, patients and family should be counseled and prepared for disease-related events such as bleeding, obstruction, infection, and pain with options for palliation that may be limited.