Editing Muscle-Invasive Bladder Cancer (section)

=== Radical Cystectomy ===

* '''See [[Cystectomy]] Chapter Notes'''
*'''<span style="color:#ff0000">Radical cystectomy with bilateral pelvic lymphadenectomy should be offered for surgically eligible patients with resectable non-metastatic (M0) muscle-invasive bladder cancer.</span>'''
**'''<span style="color:#ff0000">For non-metastatic MIBC, NAC + RC is the standard of treatment</span>'''
**'''Bladder preserving therapy has been associated with decreased survival compared to RC'''
*'''<span style="color:#ff0000">When performing a standard radical cystectomy, clinicians should remove the bladder, prostate, and seminal vesicles in males and should remove the bladder and consider removal of adjacent reproductive organs based on individual disease characteristics and need to obtain negative margins</span>'''
**Radical cystectomy involves removal of the bladder (cystectomy) along with the organs at highest risk of harboring tumors that extend beyond the bladder.
**'''<span style="color:#ff0000">Organ sparing procedures in females should be considered based on disease location and characteristics on an individual basis</span>'''
***Considering the overall low incidence of urothelial cancer involvement of the uterus, ovaries, and vagina and the absence of conclusive evidence suggesting a measurable outcome difference in removing these  organs, this scrutiny is appropriate. 
***When performing ovarian/uterine sparing procedures in women who do not desire fertility, consideration to salpingectomy should be given to reduce the risk of ovarian cancer. 
***In select women with early-stage disease and a desire to preserve fertility and/or sexual function, organ preservation may be considered as long as complete tumor resection can be achieved. 
****Preoperative counseling should be performed for patients who have invasive cancer at the bladder neck or trigone region in regards to risk of organ sparing surgery.
******More emphasis on organ preservation in females compared to 2020 and 2017 MIBC guidelines.
====Urethrectomy====
*'''<span style="color:#ff0000">Indications[https://pubmed.ncbi.nlm.nih.gov/28456635/ ★]</span>'''
*#'''<span style="color:#ff0000">All females not receiving neobladder</span>''' to reduce risk of positive surgical margin or tumor recurrence (different than CUA)
*#'''<span style="color:#ff0000">Males with invasive cancer at the apical urethral margin</span>'''
*#*Apical urethral margin assessed with
*#** Intra-operative frozen section OR
*#**Final pathology of the radical cystectomy specimen
*#*Urethrectomy can be performed at the time of cystectomy or delayed
====Sexual function preserving procedures====
*'''Should be considered for patients with organ-confined disease and absence of bladder neck, urethra, and prostate (male) involvement.'''

*Nerve-sparing should be discussed and offered in all patients who desire sexual function preservation and are sexually active, as long as it will not compromise oncologic control.
* Prostate-sparing and prostate-capsule sparing cystectomy in males
**May be offered to highly select males with negative prostatic urethral and transrectal prostate biopsies in whom fertility and sexual function are important considerations.
** Nerve sparing procedures in males may offer similar rates of sexual function preservation when compared to prostate-sparing cystectomy.
*'''Vaginal sparing radical cystectomy in females'''
**'''Can be performed when doing so will not compromise tumor control, such as in the absence of cancer in the trigone or bladder base.'''
**'''Consideration may also be given to preserving the ovaries for hormonal homeostasis, and the anterior vaginal wall and/or uterus may be preserved in the absence of direct tumor extension.'''
==== Perioperative surgical management====
*'''Clinicians should attempt to optimize patient performance status in the perioperative setting.'''
**'''Optimizing nutritional status prior to surgery; preoperative carbohydrate loading in order to diminish postoperative insulin resistance'''
**'''Smoking cessation counseling'''
**'''Consider not routinely prescribing a mechanical bowel preparation when only small bowel will be used for urinary tract reconstruction'''
*'''<span style="color:#ff0000">Perioperative pharmacologic thromboembolic prophylaxis should be given to patients undergoing radical cystectomy.[https://pubmed.ncbi.nlm.nih.gov/28456635/ ★]</span>'''
**'''<span style="color:#ff0000">Combined mechanical and pharmacologic prophylaxis is recommended.</span>'''
***Strong consideration should be given to initiating pharmacologic prophylaxis just prior to induction of anesthesia; however, the risks of bleeding need be weighed against the benefits of prophylaxis in determining the timing of heparin administration.
**'''Perioperative coverage with up to 4 weeks of treatment following surgery may be beneficial.'''
*'''μ-opioid antagonist therapy should be used to accelerate gastrointestinal recovery, unless contraindicated.'''
**'''μ-opioid antagonist therapies are contraindicated in patients who have taken opioids for ≥ 1 week prior to surgery'''
*Patients should receive detailed teaching regarding care of urinary diversion prior to discharge from the hospital
====Urinary diversion====
*'''In patients undergoing radical cystectomy, ileal conduit, continent cutaneous, and orthotopic neobladder urinary diversions should all be discussed.'''
**'''<span style="color:#ff0000">Absolute contraindications to continent diversion (6):[https://pubmed.ncbi.nlm.nih.gov/28456635/ ★]</span>'''
**#'''<span style="color:#ff0000">Insufficient bowel segment length</span>'''
**#'''<span style="color:#ff0000">Inability to perform self-catheterization</span>'''
**#*Due to inadequate motor function or psychological issues
**#'''<span style="color:#ff0000">Inadequate renal function (e.g. an eGFR < 45)</span>'''
**#*Increases the risk metabolic abnormalities as a consequence of reabsorption of urine from continent diversions
**#'''<span style="color:#ff0000">Inadequate hepatic function</span>'''
**#*Increases the risk metabolic abnormalities as a consequence of reabsorption of urine from continent diversions
**#'''<span style="color:#ff0000">Cancer at the urethral margin (specifically for orthotopic neobladder)</span>'''
**#'''<span style="color:#ff0000">Significant urethral stricture disease that is not correctable (specifically for orthotopic neobladder)</span>'''
*'''<span style="color:#ff0000">In patients undergoing an orthotopic urinary diversion, a negative urethral margin must be verified</span>'''
**Risk cancer developing in the retained urethral is 1-17%, the majority of which occur within the first 2 years after surgery.
**Risk factors include: tumor multiplicity, papillary pattern, CIS, tumor at the bladder neck, prostatic urethral involvement, and prostatic stromal invasion.
***'''<span style="color:#ff0000">Although prostate involvement is the most significant risk factor for cancer in the urethra, it should not preclude orthotopic diversion, provided that intraoperative frozen section analysis of the urethral margin is without evidence of tumor.</span>''' 
**'''Preoperative prostatic urethral biopsies have not proved to be as reliable as urethral frozen sections and should not exclude patients from orthotopic diversion.'''
==== Pelvic lymphadenectomy====

===== Indications =====
*'''<span style="color:#ff0000">Bilateral pelvic lymphadenectomy must be performed at the time of any surgery with curative intent[https://pubmed.ncbi.nlm.nih.gov/28456635/ ★]</span>'''
** Bilateral pelvic lymphadenectomy should be performed in ALL patients, including those with unilateral bladder wall involvement, due to documented crossover risk to the contralateral lymphatic chain.

===== Extent of lymphadenectomy =====
*'''<span style="color:#ff0000">When performing bilateral pelvic lymphadenectomy, at a minimum, the external and internal iliac and obturator lymph nodes should be removed[https://pubmed.ncbi.nlm.nih.gov/28456635/ ★]</span>'''
**'''To facilitate adequate staging, a standard lymphadenectomy''' (bilateral external iliac, internal iliac and obturator lymph nodes), at a minimum, '''needs to be completed with >12 lymph nodes evaluated'''
**Submission of separate nodal packets appears to facilitate identification of lymph nodes and is associated with an increased number of reported lymph nodes

====== <span style="color:#ff00ff">SWOG S1011 (NEJM 2024)  ======
* Population: 592 patients with localized muscle-invasive bladder cancer of clinical stage T2 (confined to muscle) to T4a (invading adjacent organs) with two or fewer positive nodes (N0, N1, or N2) 
* Randomized to: bilateral standard lymphadenectomy (dissection of lymph nodes on both sides of the pelvis) or extended lymphadenectomy involving removal of common iliac, presciatic, and presacral nodes.
* Primary outcome: disease-free survival
* Results:
** Median follow-up: 6.1 years
** Disease-free survival: no significant difference
** Overall survival: no significant difference
** Extended lymphadenectomy was associated with higher perioperative morbidity and mortality
* Standard or Extended Lymphadenectomy for Muscle-Invasive Bladder Cancer. Lerner et al. NEJM 2024.

====== <span style="color:#ff00ff">LEA AUO AB 25/02 (European Urology 2019)</span> ======

* Population: 401 patients with locally resectable T1G3 or muscle-invasive urothelial bladder cancer (T2-T4aM0)
* '''Randomized to limited''' (obturator, and internal and external iliac nodes) '''vs. extended LND''' (in addition, deep obturator, common iliac, presacral, paracaval, interaortocaval, and para-aortal nodes up to the inferior mesenteric artery).
* Primary outcome: recurrence-free survival
* Secondary outcomes: cancer-specific survival, overall survival, complications
* Results:
** Median number of dissected nodes: limited 19 vs. extended 31
** '''Primary outcome: no significant difference in recurrence-free survival''' (5-yr RFS 65% extended vs 59%; p=0.36)
** Secondary outcomes:
*** No significant difference in cancer-specific survival (5-yr CSS 76% vs 65%; p=0.10)
*** No significant difference in overall survival (5-yr OS 59% vs 50%; p=0.12)
*** Clavien grade ≥3 lymphoceles were more frequently reported in the extended LND group within 90 days after surgery.
* [https://pubmed.ncbi.nlm.nih.gov/30337060/ Gschwend, Jürgen E., et al.] "Extended versus limited lymph node dissection in bladder cancer patients undergoing radical cystectomy: survival results from a prospective, randomized trial." European urology 75.4 (2019): 604-611.

==== Prognosis ====
* Despite aggressive surgical therapy, ≈50% of cystectomy patients will ultimately die of disease
* '''Most recurrences will occur within the 2-3 years after cystectomy'''
* '''<span style="color:#ff0000">Prognostic factors following RC</span>'''
*# '''<span style="color:#ff0000">pT stage and presence of nodal metastasis (strongest predictors of recurrence and survival following cystectomy)</span>'''
*# '''<span style="color:#ff0000">Margin status</span>'''
*# '''<span style="color:#ff0000">Presence of lymphovascular invasion</span>'''
*#* In MIBC, presence of LVI is associated with features of aggressive disease and predicts recurrence and survival§
*#* Recall, LVI associated with progression in high-risk NMIBC
*# '''Presence of hydronephrosis'''
*#'''Molecular markers'''
*#'''Variant histology'''
*# Body mass index
*# Age
*# Gender
*# Surgical expertise
*# Hospital volume
*# Time from initial diagnosis of muscle invasion to cystectomy (particularly if there is a delay >12 weeks)
*Systemic recurrence rates by stage:
**pT2: 20-30%
**pT3: 40%
**pT4>50%
**N+: 70%
* The [https://pubmed.ncbi.nlm.nih.gov/17121885/ Bladder Cancer Research Consortium] and [https://www.mskcc.org/nomograms/bladder/post_op The International Bladder Cancer Consortium] have developed nomograms to predict recurrence following radical cystectomy
* Currently, most patients with recurrence after cystectomy are not cured with current systemic therapies
**