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

== Management ==

=== UrologySchool.com Summary ===

* '''<span style="color:#ff0000">If low-risk</span>'''
** '''<span style="color:#ff0000">Favorable</span>'''
*** '''<span style="color:#ff0000">Tumor ablation (preferred)</span>'''
** '''<span style="color:#ff0000">Unfavorable</span>''' 
*** '''<span style="color:#ff0000">Tumor ablation (optional)</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">Favorable</span>'''
*** '''<span style="color:#ff0000">Surgical removal</span>''' 
*** '''<span style="color:#ff0000">Tumor ablation (optional)</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</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 ===

* '''<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</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>'''

=== Kidney Sparing Management/Tumor Ablation ===

==== Indications ====
* '''<span style="color:#ff0000">Preferred</span>''' 
**'''<span style="color:#ff0000">Initial management for LR favorable UTUC, 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">Optional</span>''' 
**'''<span style="color:#ff0000">Initial management for LR unfavorable UTUC and select patients with HR favorable disease who have low-volume tumors or cannot undergo RNU</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>'''
**High risk of ureteric stenosis with instillation of mitomycin containing reverse thermal gel

==== Technical considerations ====
* '''Approach'''
**'''May be accomplished via a retrograde or antegrade percutaneous approach'''
***Antegrade approach typically reserved for
****Larger tumors 
****Tumor difficult to access in a retrograde fashion 
****Patients who have undergone prior radical cystectomy or urinary diversion 
*'''Tumor size'''
**'''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
**Thulium laser, holmium laser, Neodymium (Nd:YAG), and electrocautery devices (e.g., Bugbee) may all be deployed through an endoscope.
*Chemoablation 
**May be employed either through retrograde ureteral catheter instillation or percutaneous access with fluoroscopic imaging guidance
*Ureteral access sheath
**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)

==== Adjuvant therapy ====

===== Pelvicalyceal or intravesical chemotherapy following ablation of UTUC tumors =====
*'''Considered optional''' 
*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
*Prior to administration, must confirm that there is no perforation of the bladder or upper tract
*Approaches
*#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.

===== Pelvicalyceal BCG =====
*'''May be offered to patients with HR favorable UTUC after complete tumor ablation or patients with upper tract carcinoma in situ (CIS).'''
*Consists of a 6-week induction course of BCG
*'''Imperative indications'''
*#'''Solitary kidney status'''
*#'''Bilateral UTUC'''
*#'''RIsk of progression to end-stage renal disease'''

==== Repeat endoscopic evaluation ====
*'''<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.'''
=== 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.

=== Special scenarios ===

==== 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.

==== 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

=== Advanced disease ===

==== Clinical, regional node-positive (N+) ====
* '''Should initially be treated with systemic therapy.''' 
* '''Consolidative RNU or ureterectomy with lymph-node dissection may be performed in those with a partial or complete response.'''
** Pooled data from comparative outcomes utilizing NAC in patients with clinically node positive (cN+) disease supports this approach.

==== Distant metastatic disease (M+) ====
* '''Systemic therapy and alternative approaches (i.e., radiotherapy with or without chemotherapy in selected cases) should be favored for inoperable or symptomatic patients with M+ UTUC'''
* RNU or ureterectomy should not be offered as initial therapy
** Oncologic outcomes in the metastatic setting are strongly determined by response to systemic therapy, and surgical treatment has no demonstrable therapeutic efficacy for cytoreduction or as a single modality in this setting.

==== Unresectable UTUC ====
* Localized disease may be deemed unresectable or ineligible for extirpative surgical management due to significant medical comorbidities or other factors including refusal to accept surgical treatment (e.g., solitary kidney).
* Should be offered a clinical trial or best supportive care including palliative management (radiation, systemic approach, endoscopic, or ablative) for refractory symptoms such as hematuria.
** Formulating alternative care options should be approached with multi-disciplinary input with a focus on realistic goals of care such as providing means of local control for functional preservation (e.g., renal function) and palliation (e.g., bleeding, infection)
** Multi-modal approaches include combination of endoscopic management to maintain upper and lower tract function (e.g., stents, nephrostomies, ablation for bleeding and local control) in addition to systemic treatment options if available. Rarely, radiation, angioembolization, or percutaneous ablation for palliation of bleeding can be offered