Editing Muscle-Invasive Bladder Cancer (section)

== Management ==
===Patient counseling===
*For patients with newly diagnosed MIBC, curative treatment options should be discussed based on both patient comorbidity and tumor characteristics. Patient evaluation should be completed using a multidisciplinary approach.
*Prior to treatment, patients should be counselled regarding complications and the implications of treatment on quality of life (e.g., impact on continence, sexual function, fertility, bowel dysfunction, metabolic problems).
**'''Patients with'''
***'''Ileal conduit urinary diversion require external appliances and have risks of leakage or stomal complications.'''
***'''Continent cutaneous reservoirs require self-catheterization for the rest of their lives and have risks of incontinence via their stoma, stricture, pouchitis, pouch stones, and metabolic derangements.'''
***'''Neobladders have risks of incontinence (especially night-time), bladder neck contractures, voiding dysfunction with retention, and fistula formation'''
**'''Sexual dysfunction, metabolic and nutritional issues can also result from urinary diversions''' (Recall '''LSD ORGASMIC''' from [[Intestinal Segments and Urinary Diversion|Complications of Urinary Diversion]] notes)

=== Options ===

* '''<span style="color:#ff0000">Standard treatment of MIBC (clinical T2-T4a, N0, M0 disease) regardless of histologic subtype* is radical cystectomy (RC) and bilateral PLND</span>'''
** '''<span style="color:#ff0000">Timing of neoadjuvant chemotherapy (NAC) and/or radiation therapy can vary by histology</span>'''
*** '''<span style="color:#ff0000">If histology urothelial or neuroendocrine, standard treatment is NAC + RC</span>'''
**** '''Pure neuroendocrine variants of bladder cancer are relatively rare but highly aggressive''', and they typically present at high pathologic stages or with metastatic disease.
*** '''<span style="color:#ff0000">If histology small cell, standard treatment is initial chemotherapy followed by radiation or cystectomy as consolidation, if there is no metastatic disease</span>[https://www.nccn.org/professionals/physician_gls/pdf/bladder.pdf §]'''
***'''<span style="color:#ff0000">If pure non-urothelial histologic subtypes (squamous, adenocarcinoma, sarcomatoid): perioperative chemotherapy is not routinely recommended as they are perceived to generally be chemo-resistant.[https://pubmed.ncbi.nlm.nih.gov/28456635/ ★]</span>'''
* '''Alternatives'''
**'''Multi-modal/Trimodal Therapy'''
**'''Partial cystectomy and chemotherapy'''
**'''Chemotherapy alone'''
**'''Radiation alone'''

=== Neoadjuvant/adjuvant chemotherapy===

==== Neoadjuvant ====

===== Advantages =====
# '''Better tolerated before surgery, rather than after surgery when patients may experience a delay in chemotherapy administration because of complications or debilitation'''
# '''Patients who present with micrometastatic disease will receive therapy in a more timely fashion when their burden of disease is potentially low'''
# '''Downstage bulky and locally advanced tumors,''' allowing for a higher likelihood for negative surgical margins that are a known predictor of local recurrence following cystectomy
# '''Assess each individual’s response to therapy'''

===== Disadvantages =====
# '''Delay in definitive local therapy for patients who do not respond to chemotherapy and thus experience disease progression'''
# '''NAC-related toxicity (risk of venous thromboembolism, mortality)'''
# '''Non-selective nature of NAC'''

* '''NAC does not increase perioperative morbidity or complication rates'''

===== Evidence =====
* '''<span style="color:#ff0000">2 large phase III clinical trials have demonstrated an OS benefit with the use of NAC prior to RC</span>'''
** '''<span style="color:#ff00ff">SWOG 8710</span>'''
*** '''Population: 317 patients with cT2-T4aN0M0 MIBC'''
*** '''Randomized to 3 cycles of neoadjuvant MVAC (methotrexate, vinblastine, adriamycin [doxorubicin], cisplatin) + RC vs. RC alone'''
*** '''Results:'''
**** '''Absolute risk difference for pT0 status at the time of cystectomy: 23% with NAC''' (38% chemotherapy vs. 15% controls)
***** Patients who were downstaged to pT0 achieved excellent outcomes with 80% alive at 5 years compared to 40% of patients with residual disease
**** Absolute benefit median OS: 31 months (77 months MVAC vs. 46 months in RC-only group)
**** '''Absolute benefit 5-year OS: 14% (57% MVAC vs. 43% in RC-only arm). However, the survival results failed to reach statistical significance (P = .06)'''
*** [https://pubmed.ncbi.nlm.nih.gov/12944571/ Grossman, H. Barton, et al.] "Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer." New England Journal of Medicine 349.9 (2003): 859-866.
** '''<span style="color:#ff00ff">BA06 30894</span>'''
*** Population: 976 patients with MIBC
*** Randomized to neoadjuvant CMV vs. cystectomy alone
*** [https://pubmed.ncbi.nlm.nih.gov/21502557/ International Collaboration of Trialists.] "International phase III trial assessing neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: long-term results of the BA06 30894 trial." Journal of Clinical Oncology 29.16 (2011): 2171.
* '''2005 meta-analysis''' combining individual patient data from 9 trials (these 2 trials with 9 phase II trials) involving 3005 patients comparing neoadjuvant chemotherapy plus local treatment with the same local treatment alone found that '''<span style="color:#ff0000">neoadjuvant chemotherapy was associated with improved:</span>'''
** '''<span style="color:#ff0000">5-year OS: absolute benefit 5%</span>'''
** '''<span style="color:#ff0000">5-year DFS: absolute benefit 9%</span>'''
** '''Pathologic complete response (pT0) rate of 30-40% compared to 15% (SWOG trial results) without NAC'''
** Advanced Bladder Cancer (ABC) Meta-analysis Collaboration. “Neoadjuvant chemotherapy in invasive bladder cancer: update of a systematic review and meta-analysis of individual patient data advanced bladder cancer (ABC) meta-analysis collaboration.” Eur Urol. 2005 Aug;48(2):202-5; discussion 205-6. Epub 2005 Apr 21.
* '''Gemcitabine-cisplatin (GC) is a combination frequently used for NAC in MIBC due to relatively lower risk of toxicity, despite level 1 evidence for MVAC and CMV only'''
** No completed prospective randomized trials have compared GC to other regimens as NAC for MIBC. Several retrospective cohort studies suggest that there may not be a significant difference in outcome between GC and MVAC
* '''The best regimen and duration for cisplatin-based NAC remains undefined; most studies have evaluated 3-4 cycles of preoperative chemotherapy over about 3 months'''

===== Indications =====

====== AUA ======

* '''2020 AUA Muscle-Invasive Bladder Cancer Guidelines'''
** '''<span style="color:#ff0000">Prior to cystectomy, cisplatin-based NAC should be offered to eligible radical cystectomy patients</span>''', utilizing a multidisciplinary approach

====== CUA ======
*'''<span style="color:#ff0000">2019 CUA Muscle-Invasive Bladder Cancer Guidelines</span>'''
**'''<span style="color:#ff0000">All eligible patients with cT2-T4a N0 M0 urothelial carcinoma of the bladder should be encouraged to receive cisplatin-based combination chemotherapy (Gemcitabine/Cisplatin (GC), MVAC or dd-MVAC) as neoadjuvant therapy (NAC) prior to radical local therapy</span>'''

===== Contraindications =====

* '''<span style="color:#ff0000">If ineligible for cisplatin-based NAC, patients should proceed to definitive locoregional therapy (AUA/CUA)</span>'''**'''Carboplatin-based neoadjuvant chemotherapy should not be used for clinically resectable stage cT2-T4aN0 bladder cancer'''

====== AUA ======

*'''<span style="color:#ff0000">2020 AUA Muscle-Invasive Bladder Cancer Guidelines</span>'''
*#'''<span style="color:#ff0000">eGFR < 60ml/min</span>'''
*# '''<span style="color:#ff0000">Heart failure (NYHA Class > 2)</span>'''
*# '''<span style="color:#ff0000">≥Grade 2 hearing loss</span>''' (grading based on Common Terminology Criteria for Adverse Events version 4.0)
*#'''<span style="color:#ff0000">≥Grade 2 neuropathy</span>'''(grading based on Common Terminology Criteria for Adverse Events version 4.0)
*#'''<span style="color:#ff0000">Reduced performance status (ECOG ≥2 or Karnofsky performance status ≤60-70%)</span>'''

====== CUA ======
*<span style="color:#ff0000">'''2019 CUA Muscle-Invasive Bladder Cancer Guidelines'''</span> '''<span style="color:#0000ff">(HE 2 NICE)</span>'''
** '''<span style="color:#ff0000">Absolute (6):</span>'''
**# '''<span style="color:#ff0000">≥Grade </span><span style="color:#0000ff">2 H</span><span style="color:#ff0000">earing loss</span>''' (grading based on Common Terminology Criteria for Adverse Events version 4.0)
**# '''<span style="color:#0000ff">e</span><span style="color:#ff0000">GFR ≤ 50</span>''' ml/min/1.73m2
**# '''<span style="color:#ff0000">≥Grade </span><span style="color:#0000ff">2 N</span><span style="color:#ff0000">europathy</span>''' (grading based on Common Terminology Criteria for Adverse Events version 4.0)
**# '''<span style="color:#ff0000">Untreated </span><span style="color:#0000ff">I</span><span style="color:#ff0000">nfection</span>'''
**# '''<span style="color:#0000ff">C</span><span style="color:#ff0000">ardiac failure (NYHA Class > </span><span style="color:#0000ff">2)</span>'''
**# '''<span style="color:#0000ff">E</span><span style="color:#ff0000">astern Cooperative Group (ECOG) ≥</span><span style="color:#0000ff">2</span>'''
** '''Relative:'''
**# eGFR 50-60 ml/min/1.73m2
**# History of recurrent infection and concomitant immunosuppression

===== Drugs and Dosages =====
*The best regimen and duration for cisplatin-based NAC remains undefined
**No prospective randomized trials have compared gemcitabine and cisplatin to MVAC
***Retrospective studies have suggested that there is no difference between the regimens in terms of survival.
**A retrospective study found that patients who did not receive cisplatin-based chemotherapy or fewer than 3 cycles of chemotherapy had worse outcomes, compared to those that who received ≥ 3 cycles of cisplatin-based NAC, either GC or MVAC regimen at standard dose[https://pubmed.ncbi.nlm.nih.gov/30805684/]

===== <span style="color:#ff0000">Timing of radical cystectomy after NAC</span> =====
*'''<span style="color:#ff0000">Radical cystectomy is recommended as soon as possible following completion of and recovery from NAC, ideally within 12 weeks (CUA: 4-6 weeks after NAC and no more than 10 weeks), following completion of chemotherapy</span>''', unless medically inadvisable.
**Patients must be medically fit to undergo cystectomy.
**Optimal timing to proceed with cystectomy after chemotherapy has not been defined.
***Observational studies that suggest that outcomes may be worse if cystectomy is delayed more than 12 weeks after the completion of chemotherapy.
====== Adverse events ======

* '''Cisplatin eligibility is a major determinant of candidacy for NAC'''

* '''<span style="color:#ff0000">Adverse events related to cisplatin (4):</span>'''
*# '''<span style="color:#ff0000">Nephrotoxicity</span>'''
*# '''<span style="color:#ff0000">Ototoxicity</span>'''
*# '''<span style="color:#ff0000">Neurotoxicity</span>'''
*# '''<span style="color:#ff0000">Diminished cardiac function</span>'''
** '''These preclude 30-50% of MIBC patients from safe receipt of cisplatin-based chemotherapy'''
* '''No validated predictive factors or clinical characteristics (including age) associated with an increased or decreased probability of response and benefit using cisplatin-based NAC'''
** The decision regarding eligibility for cisplatin-based NAC should be based on comorbidities and performance status, including cardiac status and presence of peripheral neuropathy, hearing loss, and renal dysfunction

====== Histological considerations ======
* '''<span style="color:#ff0000">NAC is primarily derived in the urothelial carcinoma setting</span>'''
** '''Secondary analysis of SWOG 8710 found that patients with mixed tumours (squamous and glandular differentiation) derived greater benefit''' (HR 0.46) '''from neoadjuvant MVAC than patients with pure urothelial carcinoma''' (HR 0.9), compared with cystectomy[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3117124/ §]
* '''<span style="color:#ff0000">Lack of robust data supporting NAC in pure non-urothelial histologies</span>'''
** '''Exceptions are pure small cell or pure neuroendocrine carcinoma of the bladder where NAC is the mainstay of treatment'''
** '''[CUA Guidelines do not support NAC in pure non-urothelial histology, other than noted exceptions]'''

==== Adjuvant ====
* '''Patients with pT3-T4 or N+ disease are at high risk for failure following cystectomy and can be offered adjuvant chemotherapy''' to treat micrometastatic disease and to improve survival

===== Advantages =====
# '''Allows for immediate local treatment''' with cystectomy and avoids any delay in treatment in patients with chemotherapy-resistant tumors
# '''Avoids overtreatment'''; the availability of final pathology also allows clinicians to select patients at the highest risk for failure who are most likely to benefit, while sparing those who are less likely to progress from the side effects of systemic chemotherapy.

===== Disadvantages =====
* '''Often difficult or impossible for patients to undergo systemic therapy following cystectomy''' secondary to surgical deconditioning, deteriorating renal function, or perioperative complications
** ≈24-52% of patients have renal function deterioration that makes them ineligible to receive AC postoperatively depending on the criteria used.
** '''Postoperative complications may exclude ≈30% of patients who may have been eligible from receiving AC postoperatively'''

===== Evidence =====
* No single phase III trial has demonstrated an overall survival benefit with AC compared to observation
* '''2014 meta-analysis''' of 9 trials involving 945 patients '''comparing AC to standard of care found a 9% absolute survival benefit at 3 years.''' However, there were major deficiencies in the trials included such as small sample sizes, early closure of trials, limitations in statistical analysis, and differences in the way disease-free survival was defined.
** [https://pubmed.ncbi.nlm.nih.gov/24018020/ Leow, Jeffrey J., et al.] "Adjuvant chemotherapy for invasive bladder cancer: a 2013 updated systematic review and meta-analysis of randomized trials." European urology 66.1 (2014): 42-54.

===== Indications =====

====== AUA ======

* '''2020 AUA Muscle-Invasive Bladder Cancer Guidelines'''
** '''<span style="color:#ff0000">Eligible patients who have not received cisplatin-based NAC and have non-organ confined (pT3/T4and/or N+) disease at cystectomy should be offered adjuvant cisplatin-based chemotherapy (same as CUA)</span>'''

===== NAC vs. Adjuvant Chemotherapy =====
* '''The available evidence suggests perioperative chemotherapy does confer a survival benefit for bladder cancer patients, with stronger evidence available in the neoadjuvant approach'''. The optimal approach and benefit to systemic chemotherapy in the adjuvant setting remains incompletely defined, and may remain unanswered based on the difficulty with patient accrual in past trials

=== Neoadjuvant/Adjuvant Immunotherapy ===

==== Neoadjuvant ====
* PURE-01 (neoadjuvant pembrolizumab)
** Phase II trial evaluated neoadjuvant pembrolizumab in 50 patients undergoing RC for MIBC and found that 42% of patients achieved pT0[https://www.ncbi.nlm.nih.gov/pubmed/30343614 §]

==== Adjuvant ====

===== <span style="color:#ff00ff">CheckMate 274 (adjuvant nivolumab)</span> =====
* '''<span style="color:#ff0000">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</span>'''
** '''<span style="color:#ff0000">High risk defined as</span>'''
*** '''<span style="color:#ff0000">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</span>'''
*** '''<span style="color:#ff0000">Pathological stage ypT2 to ypT4a or pyN+ for patients who received neoadjuvant cisplatin</span>'''
*** 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.

=== 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
**

=== Bladder Preservation/Multimodal Therapy ===

* A multi-disciplinary team discussion is preferred for patients considering bladder preservation.
*'''Successful bladder preservation should be viewed as a multimodal therapy involving:'''
*# '''Aggressive TUR'''
*# '''Systemic chemotherapy'''
*# '''Radiation therapy'''
** Historical series have demonstrated inferior results with single modality therapy (radical TUR, chemotherapy alone, or radiation alone) compared to that of radical cystectomy.

====Patient selection====
*'''<span style="color:#ff0000">Indications[https://pubmed.ncbi.nlm.nih.gov/28456635/ ★]</span>'''
*#'''<span style="color:#ff0000">Patients with newly diagnosed non-metastatic MIBC who desire to retain their bladder</span>'''
*#'''<span style="color:#ff0000">Patients with significant comorbidities for whom radical cystectomy is not a treatment option, clinicians should offer bladder</span>''' 
*#*'''Overall, bladder preserving therapy has been associated with decreased survival compared to RC'''
*#**'''Patients who are deemed “medically fit” to undergo cystectomy should be offered cystectomy as the standard of care'''
*#*Studies that support bladder preserving strategies, as a general rule, have highly select patient populations
*#*Bladder preservation should be undertaken with the goal of curative therapy and to maintain a functionally intact bladder
*'''<span style="color:#ff0000">Ideal characteristics for bladder preservation (4):[https://pubmed.ncbi.nlm.nih.gov/28456635/ ★]</span>'''
*# '''<span style="color:#ff0000">Unifocal tumor</span>'''
*#'''<span style="color:#ff0000">No CIS</span>'''
*#'''<span style="color:#ff0000">No evidence of hydronephrosis</span>'''
*# '''<span style="color:#ff0000">A tumor that can be completely transurethrally resected</span>'''
*'''Contraindications'''
**'''Relative'''
**#'''Large tumors unable to be resected by TURBT'''
**#'''Multifocal CIS'''
**#'''T3/T4 tumors,'''
**#'''Presence of hydronephrosis'''
**#Non-urothelial carcinoma
**##Patients with adenocarcinomas, sarcomas, and squamous cell carcinomas have not been included in prospective studies of radiation-based bladder preservation
**'''Unknown how variant histology affects outcomes associated with multi-modal bladder preserving therapy'''
*'''In patients under consideration for bladder preserving therapy, maximal debulking transurethral resection of bladder tumor and assessment of multifocal disease/carcinoma in situ should be performed'''
**In multiple prospective trials, the ability to resect all tumor predicted the best response to bladder preserving therapies.
**'''Random biopsies may help ensure that there is no associated CIS.'''

==== Multi-modal/Trimodal bladder preserving therapy ====
*Most of the literature supporting multi-modal bladder preserving therapy with radical cystectomy is from one RCT and several observational studies that have compared EBRT with and without chemotherapy vs. radical cystectomy[https://pubmed.ncbi.nlm.nih.gov/38661067/]
*'''<span style="color:#ff0000">Includes (3):</span>'''
*#'''<span style="color:#ff0000">Maximal transurethral resection of bladder tumor</span>'''
*# '''<span style="color:#ff0000">Chemotherapy combined with external beam radiation therapy</span>'''
*#'''<span style="color:#ff0000">Ongoing cystoscopy to evaluate response'''
*'''Radiation sensitizing chemotherapy'''
**Should be included when using multi-modal therapy with curative intent.
***Radiation with concurrent chemotherapy is superior to radiation alone.
**Several radiosensitizing chemotherapeutic agents have been shown safe and effective for trimodal bladder cancer therapy
***'''Various regimens of neoadjuvant, concurrent and adjuvant cisplatin-based regimens (e.g., cisplatin alone, CMV, cisplatin + paclitaxel or cisplatin + gemcitabine) have been studied.'''
***Alternatives for cisplatin-ineligible patients include gemcitabine or 5-fluorouracil and mitomycin C.
***Carboplatin should not be used as a radiosensitizer unless there are contraindications to cisplatin, 5-FU, and gemcitabine.
****Carboplatin has been found to be inferior to cisplatin in multimodal bladder preserving therapy
*'''<span style="color:#ff0000">Patient selection</span>'''
** '''<span style="color:#ff0000">AUA (4):</span>'''
**# '''<span style="color:#ff0000">Unifocal</span>'''
**# '''<span style="color:#ff0000">No CIS</span>'''
**# '''<span style="color:#ff0000">No evidence of hydronephrosis</span>'''
**# '''<span style="color:#ff0000">A tumor that can be completely transurethrally resected</span>'''
**'''<span style="color:#ff0000">CUA (6):</span>'''
**# '''<span style="color:#ff0000">Unifocal</span>'''
**# '''<span style="color:#ff0000">No CIS</span>'''
**# '''<span style="color:#ff0000">No hydronephrosis</span>'''
**# '''<span style="color:#ff0000">Small (<5cm) tumour</span>'''
**#'''<span style="color:#ff0000">Good bladder function</span>'''
**# '''<span style="color:#ff0000">Patient motivated for bladder preservation</span>'''
* '''Patients with obvious T3 disease on imaging, multifocal tumors, and/or incomplete macroscopic tumor resection are also suboptimal candidates for bladder preservation'''
* '''Strategies for trimodal bladder preservation (2): split- vs. continuous-course therapy'''
** '''Split-course'''
*** '''Based on the premise of midtreatment restaging'''
**** '''Patients are administered induction chemoradiation therapy to ≈40 Gy, which is followed by restaging with cross-sectional imaging and endoscopic evaluation.'''
**** '''If persistent invasive disease [even if lower stage] is noted, RC is recommended'''. '''Those without persistent invasive disease undergo consolidative chemoradiotherapy to ≈64 Gy.'''
** '''Continuous-course'''
*** '''Involves a full course of chemoradiation therapy followed by an endoscopic restaging examination 6 months after therapy''' '''to allow time for an adequate response to therapy.'''
** '''Regardless of approach, maximal tumor debulking before trimodal therapy is critical to optimize therapeutic results'''
*'''Follow-up'''
**'''For medically operable patients receiving staged multi-modal therapy, clinicians should offer a mid-course evaluation to allow for the early selection of non-responders before consolidation radiotherapy is given'''
**'''Following completion of bladder preserving therapy, patients should have a follow up cystoscopy with biopsy to identify occult persistent malignancy, and undergo regular surveillance with CT scans, cystoscopy, and urine cytology'''
***Those who are biopsy-proven complete responders to bladder preserving protocols remain at risk for both invasive and non-invasive recurrences as well as new tumors in the upper tracts.
***No direct evidence to determine optimal frequency of surveillance, published protocols recommend:
****Cystoscopy per high-risk NMIBC schedule
****Cross-sectional imaging of the abdomen and pelvis and chest imaging every 6 months for the first 2 years
**Unclear what proportion of patients who, having initially chosen bladder preservation, ultimately require cystectomy in a non-study setting.[https://pubmed.ncbi.nlm.nih.gov/38661067/]

=== Maximal TURBT/partial cystectomy ===
* '''See [[Cystectomy]] Chapter Notes'''
*'''See [[CUA: Muscle-invasive Bladder Cancer (2019)|2019 CUA MIBC Guideline Notes]]'''
*'''Patients with MIBC who are medically fit and consent to radically cystectomy should not undergo maximal TURBT or partial cystectomy as primary curative therapy'''
**Therapies other than radical cystectomy (e.g., partial cystectomy, TURBT alone, chemotherapy alone, or radiation alone) and multi-modal bladder preserving therapy are associated with increased risk of all-cause mortality
*'''Patients who are unfit for cystectomy and multi-modal bladder preserving therapy may be offered'''
**'''Radical, maximal TURBT alone''' if they have a tumor that can be macroscopically resected completely, and for which repeat TURBT is negative '''OR'''
**'''Partial cystectomy, bilateral pelvic lymphadenectomy and perioperative chemotherapy for cisplatin-eligible patients'''
***'''If they meet the following criteria:'''
***#'''Accessible tumor location'''
***#'''Size <3cm'''
***#'''No multi-focal CIS'''
***#'''No hydronephrosis'''
***#'''Adequate bladder function'''
***#'''No residual T1 or higher stage disease'''
*Patients should be informed that approximately 40% of patients treated in this manner will ultimately require cystectomy and may have an increased risk of bladder cancer mortality.
*For patients with MIBC that have chosen maximal TURBT, no further treatment may be required if they have a tumor that can be macroscopically resected completely, and for which repeat TURBT is negative.**Studies have demonstrated that a significant proportion of patients with small MIBC’s who have a negative re-resection may be locally controlled by TURBT.
*For cisplatin-eligible patients with MIBC patients that have chosen partial cystectomy and pelvic lymphadenectomy, perioperative chemotherapy should be offered.

=== Primary chemotherapy ===
* '''Limited data on chemotherapy alone'''
** Population: 63 patients who declined cystectomy after achieving a complete response with neoadjuvant chemotherapy
** Results:
*** At a minimum of 5 years of follow-up
**** 36% of patients ultimately died of bladder cancer, of which the majority relapsed with invasive disease in the bladder
**** 64% of patients were alive and 54% exhibited an intact bladder.
** [https://pubmed.ncbi.nlm.nih.gov/18248875 Herr, Harry W.] "Outcome of patients who refuse cystectomy after receiving neoadjuvant chemotherapy for muscle-invasive bladder cancer." european urology 54.1 (2008): 126-132.

=== Primary radiotherapy ===

* '''For patients with MIBC, clinicians should not offer radiation therapy alone as a curative treatment'''
====Bladder preserving treatment failure====
*'''Patients who are medically fit and have residual or recurrent muscle-invasive disease following bladder preserving therapy should be offered radical cystectomy with bilateral pelvic lymphadenectomy'''
**≈30% of those selected for treatment by multi-modal bladder preserving therapy will have an invasive recurrence
*'''In patients who have a non-muscle invasive recurrence after bladder preserving therapy, clinicians may offer either local measures, such as TURBT with intravesical therapy, or radical cystectomy with bilateral pelvic lymphadenectomy.'''