Muscle-Invasive Bladder Cancer: Difference between revisions

Line 207:

* '''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 ====

===== 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 ====

===== 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 ====

===== 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 ====

===== Indications =====

===== AUA =====

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

* '''2020 AUA Muscle-Invasive Bladder Cancer Guidelines'''

Line 231:

* '''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/Adjuvant Immunotherapy ===

===== Neoadjuvant =====

==== 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~~ =====

==== Adjuvant ====

* '''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'''

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

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

* '''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'''

**** '''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'''

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

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

*** '''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'''

**** Enrollment of patients with upper tract urothelial carcinoma capped at approximately 20%

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

** '''Randomized 1:1 to nivolumab''' (240 mg intravenously) '''or placebo''' every 2 weeks for up to 1 year

*** Enrollment of patients with upper tract urothelial carcinoma capped at approximately 20%

** '''Outcomes:'''

* '''Randomized 1:1 to nivolumab''' (240 mg intravenously) '''or placebo''' every 2 weeks for up to 1 year

*** '''Primary: disease-free survival'''

* '''Outcomes:'''

**** Among all the patients (intention-to-treat population)

** '''Primary: disease-free survival'''

**** Among patients with a tumor programmed death ligand 1 (PD-L1) expression level of ≥1%

*** Among all the patients (intention-to-treat population)

*** Secondary: survival free from recurrence outside the urothelial tract, overall survival, and disease-specific survival

*** Among patients with a tumor programmed death ligand 1 (PD-L1) expression level of ≥1%

** '''Results'''

** Secondary: survival free from recurrence outside the urothelial tract, overall survival, and disease-specific survival

*** '''Median follow-up: ≈20 months'''

* '''Results'''

*** '''Primary outcome: disease-free survival'''

** '''Median follow-up: ≈20 months'''

**** '''Disease-free survival benefit: 10 months''' (21 months nivolumab vs. 11 months placebo)

** '''Primary outcome: disease-free survival'''

****Absolute disease-free survival benefit at 6 months:

*** '''Disease-free survival benefit: 10 months''' (21 months nivolumab vs. 11 months placebo)

***** All patients: 15% (75% adjuvant nivolumab vs. 60% placebo)

***Absolute disease-free survival benefit at 6 months:

***** PD-L1 patients (40% of all patients): 18% (74% adjuvant nivolumab vs. 56% placebo)

**** All patients: 15% (75% adjuvant nivolumab vs. 60% placebo)

****'''In patients with upper tract urothelial carcinoma, hazard ratio in favour of placebo'''

**** PD-L1 patients (40% of all patients): 18% (74% adjuvant nivolumab vs. 56% placebo)

*** Secondary outcomes:

***'''In patients with upper tract urothelial carcinoma, hazard ratio in favour of placebo'''

**** Distant metastasis-free survival improved with adjuvant nivolumab in both groups

** Secondary outcomes:

**** Overall survival and disease-specific survival not reported

*** Distant metastasis-free survival improved with adjuvant nivolumab in both groups

**** Adverse events

*** Overall survival and disease-specific survival not reported

***** Most common adverse events in nivolumab group: pruritis (23%), fatigue (17%), and diarrhea (17%)

*** Adverse events

***** 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%)

**** Most common adverse events in nivolumab group: pruritis (23%), fatigue (17%), and diarrhea (17%)

***** 3/351 (1%) treatment-related deaths in nivolumab group, 2 from pneumonitis, 1 from bowel perforation

**** 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%)

** [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.

**** 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 ===

@@ Line 207: / Line 207: @@
 * '''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 ====
+===== 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 ====
+===== 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 ====
+===== 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 ====
+===== Indications =====
-===== AUA =====
+====== AUA ======
 * '''2020 AUA Muscle-Invasive Bladder Cancer Guidelines'''
@@ Line 231: / Line 231: @@
 * '''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/Adjuvant Immunotherapy ===
-===== Neoadjuvant =====
+==== 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 =====
+==== 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:#ff00ff">CheckMate 274 (adjuvant nivolumab)</span> =====
-*** '''<span style="color:#ff0000">High risk defined as</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">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">High risk defined as</span>'''
-**** '''<span style="color:#ff0000">Pathological stage ypT2 to ypT4a or pyN+ for patients who received neoadjuvant cisplatin</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>'''
-**** Enrollment of patients with upper tract urothelial carcinoma capped at approximately 20%
+*** '''<span style="color:#ff0000">Pathological stage ypT2 to ypT4a or pyN+ for patients who received neoadjuvant cisplatin</span>'''
-** '''Randomized 1:1 to nivolumab''' (240 mg intravenously) '''or placebo''' every 2 weeks for up to 1 year
+*** Enrollment of patients with upper tract urothelial carcinoma capped at approximately 20%
-** '''Outcomes:'''
+* '''Randomized 1:1 to nivolumab''' (240 mg intravenously) '''or placebo''' every 2 weeks for up to 1 year
-*** '''Primary: disease-free survival'''
+* '''Outcomes:'''
-**** Among all the patients (intention-to-treat population)
+** '''Primary: disease-free survival'''
-**** Among patients with a tumor programmed death ligand 1 (PD-L1) expression level of ≥1%
+*** Among all the patients (intention-to-treat population)
-*** Secondary: survival free from recurrence outside the urothelial tract, overall survival, and disease-specific survival
+*** Among patients with a tumor programmed death ligand 1 (PD-L1) expression level of ≥1%
-** '''Results'''
+** Secondary: survival free from recurrence outside the urothelial tract, overall survival, and disease-specific survival
-*** '''Median follow-up: ≈20 months'''
+* '''Results'''
-*** '''Primary outcome: disease-free survival'''
+** '''Median follow-up: ≈20 months'''
-**** '''Disease-free survival benefit: 10 months''' (21 months nivolumab vs. 11 months placebo)
+** '''Primary outcome: disease-free survival'''
-****Absolute disease-free survival benefit at 6 months:
+*** '''Disease-free survival benefit: 10 months''' (21 months nivolumab vs. 11 months placebo)
-***** All patients: 15% (75% adjuvant nivolumab vs. 60% placebo)
+***Absolute disease-free survival benefit at 6 months:
-***** PD-L1 patients (40% of all patients): 18% (74% adjuvant nivolumab vs. 56% placebo)
+**** All patients: 15% (75% adjuvant nivolumab vs. 60% placebo)
-****'''In patients with upper tract urothelial carcinoma, hazard ratio in favour of placebo'''
+**** PD-L1 patients (40% of all patients): 18% (74% adjuvant nivolumab vs. 56% placebo)
-*** Secondary outcomes:
+***'''In patients with upper tract urothelial carcinoma, hazard ratio in favour of placebo'''
-**** Distant metastasis-free survival improved with adjuvant nivolumab in both groups
+** Secondary outcomes:
-**** Overall survival and disease-specific survival not reported
+*** Distant metastasis-free survival improved with adjuvant nivolumab in both groups
-**** Adverse events
+*** Overall survival and disease-specific survival not reported
-***** Most common adverse events in nivolumab group: pruritis (23%), fatigue (17%), and diarrhea (17%)
+*** Adverse events
-***** 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%)
+**** Most common adverse events in nivolumab group: pruritis (23%), fatigue (17%), and diarrhea (17%)
-***** 3/351 (1%) treatment-related deaths in nivolumab group, 2 from pneumonitis, 1 from bowel perforation
+**** 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%)
-** [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.
+**** 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 ===