Muscle-Invasive Bladder Cancer: Difference between revisions

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[[Category:Bladder Cancer]]

'''See [[AUA & ASCO & ASTRO & SUO: Muscle-invasive Bladder Cancer (~~2020~~)|~~2020~~ AUA MIBC Guideline Notes]]'''

'''See [[AUA & ASCO & ASTRO & SUO: Muscle-invasive Bladder Cancer (2024)|2024 AUA MIBC Guideline Notes]]'''

'''See [[CUA: Muscle-invasive Bladder Cancer (2019)|2019 CUA MIBC Guideline Notes]]'''

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**'''≈20-25% of patients will present with muscle-invasive bladder cancer (MIBC)'''

*'''≈20% of patients initially diagnosed with NMIBC will progress to MIBC'''

** '''Patients who initially present with NMIBC and progress to MIBC have been found to have a worse prognosis than patients who initially present with MIBC'''

** ≈50% or more patients with high-risk NMIBC can progress to invasive disease.

**'''Patients who initially present with NMIBC and progress to MIBC have been found to have a worse prognosis than patients who initially present with MIBC'''

== Prognosis ==

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***'''Prior smokers may benefit from a chest CT;''' non-smokers should have a minimum of a chest x-ray (with posterior-anterior and lateral images).****Non-smokers also may benefit from CT imaging to evaluate for metastatic cancer.

**Bone scan

***Indications (2):***#Elevated alkaline phosphatase

***Indications (2):

***#Elevated alkaline phosphatase

***#Presence of bone pain symptoms

** PET imaging

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*** '''If histology small cell, standard treatment is initial chemotherapy followed by radiation or cystectomy as consolidation, if there is no metastatic disease[https://www.nccn.org/professionals/physician_gls/pdf/bladder.pdf §]'''

***'''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/ ★]'''

* Alternatives

* '''Alternatives'''

**'''Multi-modal/Trimodal Therapy'''

**'''Partial cystectomy and chemotherapy'''

**'''Chemotherapy alone'''

**'''Radiation alone'''

=== Neoadjuvant/adjuvant chemotherapy===

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=== Neoadjuvant/Adjuvant Immunotherapy ===

==== Options (3) ====

# '''Nivolumab (adjuvant)'''

# '''Pembrolizumab (adjuvant)'''

# '''Darvalumab (neoadjuvant/adjuvant)'''

==== Neoadjuvant ====

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===== CheckMate 274 (adjuvant nivolumab) =====

* '''~~~~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~~~~'''

* '''=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'''

** '''~~~~High risk defined as~~~~'''

** '''High risk defined as'''

*** '''~~~~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~~~~'''

*** '''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'''

*** '''~~~~Pathological stage ypT2 to ypT4a or pyN+ for patients who received neoadjuvant cisplatin~~~~'''

*** '''Pathological stage ypT2 to ypT4a or pyN+ for patients who received neoadjuvant cisplatin'''

*** 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

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**** 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.

===== AMBASSADOR (adjuvant pembrolizumab) =====

* '''Population: 702 patients with muscle-invasive urothelial carcinoma of the urinary tract or lymph node–positive disease, with or without neoadjuvant cisplatin-based therapy'''

* Randomized 1:1 to pembrolizumab (200 mg intravenously) every 3 weeks for up to 1 year or observation

* Outcomes:

** Co-Primary: disease-free survival and overall survival

* Results

** Median follow-up: ≈45 months

** Co-Primary outcome:

*** Disease-free benefit: ≈5 months (median 45 months pembrolizumab vs. 40 months observation)

***Overall survival benefit at 3 years: -1.1% (60.8% pembrolizumab vs. 61.9% in the observation group)

* [https://pubmed.ncbi.nlm.nih.gov/39282902/ Apolo, Andrea B., et al. "Adjuvant pembrolizumab versus observation in muscle-invasive urothelial carcinoma." ''New England Journal of Medicine'' (2024).]

==== Neoadjuvant/Adjuvant ====

===== NIAGARA (neoadjuvant/adjuvant darvalumab) =====

* Population: 503 patients with muscle-invasive bladder cancer, cT2-4a, N0-1, M0, and eligible for cisplatin-based chemotherapy

* Randomized 1:1 to four cycles of neoadjuvant durvalumab with gemcitabine–cisplatin every 3 weeks, followed by radical cystectomy and then up to eight cycles of adjuvant durvalumab administered intravenously every 4 weeks vs. neoadjuvant gemcitabine–cisplatin followed by radical cystectomy alone

* Co-Primary Outcomes:

** Pathological complete response

** Event-free survival, defined as the time from randomization to progressive disease that precluded radical cystectomy, the first recurrence of disease after radical cystectomy, the expected date of surgery (in patients who did not undergo radical cystectomy), or death from any cause.

* Results

** Pathological complete response benefit: 8% (33.8% darvalumab vs. 25.8% comparison)

** Event-free survival at 24 months benefit: 8% (67.8% darvalumab vs. 59.8% comparison)

* [https://pubmed.ncbi.nlm.nih.gov/39282910/ Powles, Thomas, et al. "Perioperative durvalumab with neoadjuvant chemotherapy in operable bladder cancer." ''The New England journal of medicine'' (2024): 1-14.]

=== Radical Cystectomy ===

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*'''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'''

**Radical cystectomy involves removal of the bladder (cystectomy) along with the organs at highest risk of harboring tumors that extend beyond the bladder.

**'''In select ~~females~~ 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.~~'''~~***More emphasis on organ preservation in females compared to 2017 MIBC guidelines.

**'''Organ sparing procedures in females should be considered based on disease location and characteristics on an individual basis'''

***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====

*'''Indications'''

*'''Indications[https://pubmed.ncbi.nlm.nih.gov/28456635/ ★]'''

*#'''All females not receiving neobladder''' to reduce risk of positive surgical margin or tumor recurrence (different than CUA)

*#'''Males with invasive cancer at the apical urethral margin'''

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==== 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

**'''Optimizing nutritional status prior to surgery; preoperative carbohydrate loading in order to diminish postoperative insulin resistance'''

**Smoking cessation counseling

**'''Smoking cessation counseling'''

**'''Consider not routinely prescribing a mechanical bowel preparation when only small bowel will be used for urinary tract reconstruction'''

*'''Perioperative pharmacologic thromboembolic prophylaxis should be given to patients undergoing radical cystectomy.'''

*'''Perioperative pharmacologic thromboembolic prophylaxis should be given to patients undergoing radical cystectomy.[https://pubmed.ncbi.nlm.nih.gov/28456635/ ★]'''

**'''Combined mechanical and pharmacologic prophylaxis is recommended.'''

***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.

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====Urinary diversion====

*'''In patients undergoing radical cystectomy, ileal conduit, continent cutaneous, and orthotopic neobladder urinary diversions should all be discussed.'''

**'''Absolute contraindications to continent diversion (6):'''

**'''Absolute contraindications to continent diversion (6):[https://pubmed.ncbi.nlm.nih.gov/28456635/ ★]'''

**#'''Insufficient bowel segment length'''

**#'''Inability to perform self-catheterization'''

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**'''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====

*'''Bilateral pelvic lymphadenectomy must be performed at the time of any surgery with curative intent'''

===== Indications =====

*'''Bilateral pelvic lymphadenectomy must be performed at the time of any surgery with curative intent[https://pubmed.ncbi.nlm.nih.gov/28456635/ ★]'''

** 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.

*'''When performing bilateral pelvic lymphadenectomy, at a minimum, the external and internal iliac and obturator lymph nodes should be removed'''

===== Extent of lymphadenectomy =====

*'''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/ ★]'''

**'''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

==== '''~~Prognosis~~''' ====

====== 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.

====== LEA AUO AB 25/02 (European Urology 2019) ======

* 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

* '''Most recurrences will occur within the 2-3 years after cystectomy'''

* '''Prognostic factors following RC'''

*# '''pT stage and presence of nodal metastasis (strongest predictors of recurrence and survival following cystectomy)'''

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*#* 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

*# ~~Variant histology~~

*# '''Presence of hydronephrosis'''

*# Molecular markers

*#'''Molecular markers'''

*#'''Variant histology'''

*# Body mass index

*# Presence of hydronephrosis

*# Age

*# Gender

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* 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====

*'''~~For patients~~ with newly diagnosed non-metastatic MIBC who desire to retain their bladder~~, and for those~~ with significant comorbidities for whom radical cystectomy is not a treatment option, clinicians should offer bladder ~~preserving therapy when clinically appropriate~~'''

*'''Indications[https://pubmed.ncbi.nlm.nih.gov/28456635/ ★]'''

**'''Overall, bladder preserving therapy has been associated with decreased survival compared to RC'''

*#'''Patients with newly diagnosed non-metastatic MIBC who desire to retain their bladder'''

**Studies that support bladder preserving strategies, as a general rule, have highly select patient populations

*#'''Patients with significant comorbidities for whom radical cystectomy is not a treatment option, clinicians should offer bladder'''

*'''Ideal characteristics for bladder preservation (4):'''

*#*'''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

*'''Ideal characteristics for bladder preservation (4):[https://pubmed.ncbi.nlm.nih.gov/28456635/ ★]'''

*# '''Unifocal tumor'''

*#'''No CIS'''

*#'''No evidence of hydronephrosis'''

*# '''A tumor that can be completely transurethrally resected'''

*#*'''~~CUA also mentions tumour size <5cm~~, ~~good bladder capacity~~, and ~~motivated patient~~'''

*'''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.'''

* '''Patients with large tumors unable to be resected by TURBT, multifocal CIS, T3/T4 tumors, and/or hydronephrosis are not ideal candidates for any type of bladder preserving therapy.'''

*'''Histological considerations'''

**'''Unknown how variant histology affects outcomes associated with multi-modal bladder preserving therapy.'''

** Patients with adenocarcinomas, sarcomas, and squamous cell carcinomas have not been included in prospective studies of radiation-based bladder preservation and thus should not receive this therapy unless medically unfit for cystectomy.

*'''Patients who are deemed “medically fit” to undergo cystectomy should be offered cystectomy as the standard of care; however, bladder preservation is a reasonable option for those who are highly selected and counseled appropriately. Patients who are medically unfit for surgery or who refuse surgery can be considered for bladder preservation.'''

* Bladder preservation should be undertaken with the goal of curative therapy and to maintain a functionally intact bladder

* '''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.

==== 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/]

*'''Includes (3):'''

*#'''Maximal transurethral resection of bladder tumor'''

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**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.'''

**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.

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*'''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, ~~clinicians~~ should ~~perform~~ regular surveillance with CT scans, cystoscopy, and urine cytology'''

**'''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~~: every 3 months during the first year, every 4~~-~~6 months in the second, and every 6-12 months thereafter~~

***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/]

~~==== Other treatments ====~~

=== Maximal TURBT/partial cystectomy ===

===== Maximal TURBT/partial cystectomy =====

* '''See [[Cystectomy]] Chapter Notes'''

*'''See [[CUA: Muscle-invasive Bladder Cancer (2019)|2019 CUA MIBC Guideline Notes]]'''

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*For cisplatin-eligible patients with MIBC patients that have chosen partial cystectomy and pelvic lymphadenectomy, perioperative chemotherapy should be offered.

===== Primary chemotherapy =====

=== Primary chemotherapy ===

* ~~RC remains the standard of care in patients who have had a complete response to neoadjuvant therapy; however, patients have refused cystectomy in this setting.~~

* '''Limited data on chemotherapy alone'''

** Population: 63 patients who declined cystectomy after achieving a complete response with neoadjuvant chemotherapy

** Results:

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**** 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'''

=== 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'''

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* Wein AJ, Kavoussi LR, Partin AW, Peters CA (eds): CAMPBELL-WALSH UROLOGY, ed 11. Philadelphia, Elsevier, 2015, chap 94

*[https://pubmed.ncbi.nlm.nih.gov/28456635/ Chang, Sam S., et al. "Treatment of non-metastatic muscle-invasive bladder cancer: AUA/ASCO/ASTRO/SUO guideline." ''The Journal of urology'' 198.3 (2017): 552-559.]

*[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6737737/ Kulkarni, Girish S., et al. "Canadian Urological Association guideline: Muscle-invasive bladder cancer." ''Canadian Urological Association Journal'' 13.8 (2019): 230.]

@@ Line 1: / Line 1: @@
 [[Category:Bladder Cancer]]
-'''See [[AUA & ASCO & ASTRO & SUO: Muscle-invasive Bladder Cancer (2020)|2020 AUA MIBC Guideline Notes]]'''
+'''See [[AUA & ASCO & ASTRO & SUO: Muscle-invasive Bladder Cancer (2024)|2024 AUA MIBC Guideline Notes]]'''
 '''See [[CUA: Muscle-invasive Bladder Cancer (2019)|2019 CUA MIBC Guideline Notes]]'''
@@ Line 11: / Line 11: @@
 **'''<span style="color:#ff0000">≈20-25% of patients will present with muscle-invasive bladder cancer (MIBC)</span>'''
 *'''≈20% of patients initially diagnosed with NMIBC will progress to MIBC'''
-** '''Patients who initially present with NMIBC and progress to MIBC have been found to have a worse prognosis than patients who initially present with MIBC'''
+** ≈50% or more patients with high-risk NMIBC can progress to invasive disease.
+**'''Patients who initially present with NMIBC and progress to MIBC have been found to have a worse prognosis than patients who initially present with MIBC'''
 == Prognosis ==
@@ Line 51: / Line 52: @@
 ***'''Prior smokers may benefit from a chest CT;''' non-smokers should have a minimum of a chest x-ray (with posterior-anterior and lateral images).****Non-smokers also may benefit from CT imaging to evaluate for metastatic cancer.
 **Bone scan
-***Indications (2):***#Elevated alkaline phosphatase
+***Indications (2):
+***#Elevated alkaline phosphatase
 ***#Presence of bone pain symptoms
 ** PET imaging
@@ Line 95: / Line 97: @@
 *** '''<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
+* '''Alternatives'''
+**'''Multi-modal/Trimodal Therapy'''
+**'''Partial cystectomy and chemotherapy'''
+**'''Chemotherapy alone'''
+**'''Radiation alone'''
 === Neoadjuvant/adjuvant chemotherapy===
@@ Line 234: / Line 240: @@
 === Neoadjuvant/Adjuvant Immunotherapy ===
+==== Options (3) ====
+# '''<span style="color:#ff0000">Nivolumab (adjuvant)'''
+# '''<span style="color:#ff0000">Pembrolizumab (adjuvant)'''
+# '''<span style="color:#ff0000">Darvalumab (neoadjuvant/adjuvant)'''
 ==== Neoadjuvant ====
@@ Line 242: / Line 254: @@
 ===== <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>'''
+* '''=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 style="color:#ff0000">High risk defined as</span>'''
+** '''High risk defined as'''
-*** '''<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>'''
+*** '''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 style="color:#ff0000">Pathological stage ypT2 to ypT4a or pyN+ for patients who received neoadjuvant cisplatin</span>'''
+*** '''Pathological stage ypT2 to ypT4a or pyN+ for patients who received neoadjuvant cisplatin'''
 *** 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
@@ Line 269: / Line 281: @@
 **** 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.
+===== <span style="color:#ff00ff">AMBASSADOR (adjuvant pembrolizumab)</span> =====
+* '''Population: 702 patients with muscle-invasive urothelial carcinoma of the urinary tract or lymph node–positive disease, with or without neoadjuvant cisplatin-based therapy'''
+* Randomized 1:1 to pembrolizumab (200 mg intravenously) every 3 weeks for up to 1 year or observation
+* Outcomes:
+** Co-Primary: disease-free survival and overall survival
+* Results
+** Median follow-up: ≈45 months
+** Co-Primary outcome:
+*** Disease-free benefit: ≈5 months (median 45 months pembrolizumab vs. 40 months observation)
+***Overall survival benefit at 3 years: -1.1% (60.8% pembrolizumab vs. 61.9% in the observation group)
+* [https://pubmed.ncbi.nlm.nih.gov/39282902/ Apolo, Andrea B., et al. "Adjuvant pembrolizumab versus observation in muscle-invasive urothelial carcinoma." ''New England Journal of Medicine'' (2024).]
+==== Neoadjuvant/Adjuvant ====
+===== <span style="color:#ff00ff">NIAGARA (neoadjuvant/adjuvant darvalumab)</span> =====
+* Population: 503 patients with muscle-invasive bladder cancer, cT2-4a, N0-1, M0, and eligible for cisplatin-based chemotherapy
+* Randomized 1:1 to four cycles of neoadjuvant durvalumab with gemcitabine–cisplatin every 3 weeks, followed by radical cystectomy and then up to eight cycles of adjuvant durvalumab administered intravenously every 4 weeks vs. neoadjuvant gemcitabine–cisplatin followed by radical cystectomy alone
+* Co-Primary Outcomes:
+** Pathological complete response
+** Event-free survival, defined as the time from randomization to progressive disease that precluded radical cystectomy, the first recurrence of disease after radical cystectomy, the expected date of surgery (in patients who did not undergo radical cystectomy), or death from any cause.
+* Results
+** Pathological complete response benefit: 8% (33.8% darvalumab vs. 25.8% comparison)
+** Event-free survival at 24 months benefit: 8% (67.8% darvalumab vs. 59.8% comparison)
+* [https://pubmed.ncbi.nlm.nih.gov/39282910/ Powles, Thomas, et al. "Perioperative durvalumab with neoadjuvant chemotherapy in operable bladder cancer." ''The New England journal of medicine'' (2024): 1-14.]
 === Radical Cystectomy ===
@@ Line 278: / Line 316: @@
 *'''<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.
-**'''In select females 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.'''***More emphasis on organ preservation in females compared to 2017 MIBC guidelines.
+**'''<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</span>'''
+*'''<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>'''
@@ Line 299: / Line 342: @@
 ==== 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
+**'''Optimizing nutritional status prior to surgery; preoperative carbohydrate loading in order to diminish postoperative insulin resistance'''
-**Smoking cessation counseling
+**'''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.</span>'''
+*'''<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.
@@ Line 311: / Line 354: @@
 ====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):</span>'''
+**'''<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>'''
@@ Line 327: / Line 370: @@
 **'''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====
-*'''<span style="color:#ff0000">Bilateral pelvic lymphadenectomy must be performed at the time of any surgery with curative intent</span>'''
+===== 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.
-*'''<span style="color:#ff0000">When performing bilateral pelvic lymphadenectomy, at a minimum, the external and internal iliac and obturator lymph nodes should be removed</span>'''
+===== 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
-==== '''Prognosis''' ====
+====== <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
+* '''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>'''
@@ Line 342: / Line 415: @@
 *#* 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
-*# Variant histology
+*# '''Presence of hydronephrosis'''
-*# Molecular markers
+*#'''Molecular markers'''
+*#'''Variant histology'''
 *# Body mass index
-*# Presence of hydronephrosis
 *# Age
 *# Gender
@@ Line 363: / Line 436: @@
 * 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">For patients with newly diagnosed non-metastatic MIBC who desire to retain their bladder, and for those with significant comorbidities for whom radical cystectomy is not a treatment option, clinicians should offer bladder preserving therapy when clinically appropriate</span>'''
+*'''<span style="color:#ff0000">Indications[https://pubmed.ncbi.nlm.nih.gov/28456635/ ★]</span>'''
-**'''Overall, bladder preserving therapy has been associated with decreased survival compared to RC'''
+*#'''<span style="color:#ff0000">Patients with newly diagnosed non-metastatic MIBC who desire to retain their bladder</span>'''
-**Studies that support bladder preserving strategies, as a general rule, have highly select patient populations
+*#'''<span style="color:#ff0000">Patients with significant comorbidities for whom radical cystectomy is not a treatment option, clinicians should offer bladder</span>'''
-*'''<span style="color:#ff0000">Ideal characteristics for bladder preservation (4):</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>'''
-*#*'''<span style="color:#ff0000">CUA also mentions tumour size <5cm, good bladder capacity, and motivated patient</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.'''
-* '''Patients with large tumors unable to be resected by TURBT, multifocal CIS, T3/T4 tumors, and/or hydronephrosis are not ideal candidates for any type of bladder preserving therapy.'''
-*'''Histological considerations'''
-**'''Unknown how variant histology affects outcomes associated with multi-modal bladder preserving therapy.'''
-** Patients with adenocarcinomas, sarcomas, and squamous cell carcinomas have not been included in prospective studies of radiation-based bladder preservation and thus should not receive this therapy unless medically unfit for cystectomy.
-*'''Patients who are deemed “medically fit” to undergo cystectomy should be offered cystectomy as the standard of care; however, bladder preservation is a reasonable option for those who are highly selected and counseled appropriately. Patients who are medically unfit for surgery or who refuse surgery can be considered for bladder preservation.'''
-* Bladder preservation should be undertaken with the goal of curative therapy and to maintain a functionally intact bladder
-* '''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.
 ==== 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>'''
@@ Line 398: / Line 477: @@
 **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.'''
+**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.
@@ Line 426: / Line 506: @@
 *'''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, clinicians should perform regular surveillance with CT scans, cystoscopy, and urine cytology'''
+**'''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: every 3 months during the first year, every 4-6 months in the second, and every 6-12 months thereafter
+***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/]
-==== Other treatments ====
+=== Maximal TURBT/partial cystectomy ===
-===== Maximal TURBT/partial cystectomy =====
 * '''See [[Cystectomy]] Chapter Notes'''
 *'''See [[CUA: Muscle-invasive Bladder Cancer (2019)|2019 CUA MIBC Guideline Notes]]'''
@@ Line 452: / Line 532: @@
 *For cisplatin-eligible patients with MIBC patients that have chosen partial cystectomy and pelvic lymphadenectomy, perioperative chemotherapy should be offered.
-===== Primary chemotherapy =====
+=== Primary chemotherapy ===
-* RC remains the standard of care in patients who have had a complete response to neoadjuvant therapy; however, patients have refused cystectomy in this setting.
+* '''Limited data on chemotherapy alone'''
 ** Population: 63 patients who declined cystectomy after achieving a complete response with neoadjuvant chemotherapy
 ** Results:
@@ Line 460: / Line 540: @@
 **** 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'''
+=== 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'''
@@ Line 499: / Line 582: @@
 * Wein AJ, Kavoussi LR, Partin AW, Peters CA (eds): CAMPBELL-WALSH UROLOGY, ed 11. Philadelphia, Elsevier, 2015, chap 94
 *[https://pubmed.ncbi.nlm.nih.gov/28456635/ Chang, Sam S., et al. "Treatment of non-metastatic muscle-invasive bladder cancer: AUA/ASCO/ASTRO/SUO guideline." ''The Journal of urology'' 198.3 (2017): 552-559.]
+*[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6737737/ Kulkarni, Girish S., et al. "Canadian Urological Association guideline: Muscle-invasive bladder cancer." ''Canadian Urological Association Journal'' 13.8 (2019): 230.]