Non-Muscle Invasive Bladder Cancer: Difference between revisions

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[[Category:Bladder Cancer]]

~~'''~~See [[CUA & AUA: Non-muscle Invasive Bladder Cancer (2021 CUA & ~~2020~~ AUA)|~~2016~~ AUA/2021 CUA NMBIC Guideline Notes]]'''

'''See''' '''[[CUA & AUA: Non-muscle Invasive Bladder Cancer (2021 CUA & 2024 AUA)|2024 AUA/2021 CUA NMBIC]] Guideline Notes'''

'''The notes below apply to urothelial carcinoma, not other histologies of bladder cancer such as pure squamous cell, adenocarcinoma, small cell, or other pure non-urothelial carcinomas of the bladder'''

== ~~Diagnosis of NMIBC~~ ==

== Epidemiology ==

* '''See [[Bladder Cancer: Diagnosis and Evaluation|Bladder Cancer: Diagnosis & Evaluation]]'''

* '''≈75-80% of bladder cancer patients will present with NMIBC while ≈20-25% will present with MIBC and/or metastatic disease'''

* '''≈75-80% of patients will present with NMIBC ~~and~~ ≈20-25% will present with MIBC and/or metastatic disease'''

* '''Of patients with NMIBC, 70% are Ta, 20% are T1, and 10% are CIS'''

** '''Of patients with NMIBC, 70% are Ta, 20% are T1, and 10% are CIS'''

** Majority of Ta tumours are low-grade

*** Majority of Ta tumours are low-grade

** T1 tumours are almost always high-grade (2% of T1 tumours are classified low-grade)

*** T1 tumours are almost always high-grade (2% of T1 tumours are classified low-grade)

** Adjusted incidence of stage Ta has significantly increased, while stages Tis and T1 have slightly decreased

*** Adjusted incidence of stage Ta has significantly increased, while stages Tis and T1 have slightly decreased

== ~~Prognosis of NMIBC~~ ==

== Diagnosis and Evaluation ==

* '''~~Recurrence rate: ≈60-70%'''~~

* '''See [[Bladder Cancer: Diagnosis and Evaluation|Bladder Cancer: Diagnosis & Evaluation]]'''

* '''Progression rate to a higher grade or stage: ≈20-30%'''

* '''Risk factors for recurrence and progression in NMIBC''' (2015 CUA NMIBC Guidelines) '''(6): Girish''' (or other name with G) '''Sends Sexy Notes, Chocolates, and Roses'''

*# '''Grade (most important)'''

*#* '''Grade more important than stage''' (unlike other cancers where stage is more important)

*#** '''High-grade tumors progress with similar frequency regardless of whether they are invasive (T1) or non-invasive (Ta)'''

*#** '''Stage Ta are usually LG; however, ≈7% of Ta disease is HG'''

*# '''Stage (second most important)'''

*#* TaLG: high recurrence rate (≈55%), but much lower stage '''progression rate ≈6%'''

*#* T1HG: high recurrence rate (≈45%) and high progression rate ≈17% [~~different numbers than Chapter 93]~~

*# '''Size of tumour (>3 cm)'''

*# '''Number of tumours'''

*# '''Recurrence rate prior''' (>1 per year)

*# '''CIS'''

*#* If CIS is treated only with TURBT,

*#** High risk of recurrence (as high as 90%)

*#** High risk (> 50%) for progressing to muscle-invasive disease.

*#* Even patients with a complete response to intravesical BCG will experience progression in 30% to 40% of cases on longitudinal follow-up

*#* Concomitant CIS is associated with significantly increased risk of disease progression and disease-specific mortality

** '''2016 AUA NMIBC Guidelines:''' separated into recurrence vs. progression, same factors as CUA):

*** '''Recurrence: prior recurrence rate, number of tumours, tumour size'''

*** '''Progression: T-stage, grade, presence of CIS'''

** Probability of recurrence and progression of NMIBC can be calculated based on these 6 factors with the [~~http://www.eortc.be/tools/bladdercalculator/ European Organization for Research and Treatment of~~ Cancer ~~(EORTC) risk tables].~~

*** These tables were developed and based on individual patient data from 2596 patients diagnosed with Ta/T1 tumours who were randomized in 7 EORTC trials.

*** Note that the EORTC risk calculator likely overestimates the risk of recurrence and progression, as very few of the patients in these prospective trials received intravesical BCG

* '''Other risk factors'''

** '''Mentioned in [https://pubmed.ncbi.nlm.nih.gov/33938798/ 2021 CUA NMIBC Guidelines] (5):'''

**# '''Age > 70 yr'''

**# '''Extensive invasion of the lamina propria'''

**#* Extent of invasion of T1 tumours has been evaluated using two different criteria:

**## Micrometric: evaluates the millimetric extent of invasion into the lamina propria

**## Microanatomic: evaluates the level of invasion in relation to the muscularis mucosa (T1a – no muscularis mucosa invasion, T1b – invasion at the level of the muscularis mucosa and T1c – invasion beyond the muscularis mucosa)

**#*No single approach has been universally adopted

**# '''Lymphovascular invasion (LVI)'''

**#* '''Retrospective studies demonstrate that the presence of LVI is an independent factor for progression in patients with high-risk NMIBC'''.

**#** '''Use of LVI as a prognostic variable on transurethral resection (TUR) specimen requires prospective validation'''

**#* In NIMBC, LVI is associated with increased risk of recurrence and progression in BCG-treated patients with T1 NMIBC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4719750/ §]

**# '''Aggressive histological variants such as (3): ~~micropapillary, plasmacytoid,~~ and ~~sarcomatoid'''~~

**#* See Bladder Cancer: ~~Pathology~~ & ~~TNM Staging~~

**#* '''Associated with under-staging and early progression to muscle invasive disease'''

**# '''First assessment after TURBT'''

**#* Persistent disease at the first surveillance cystoscopy after induction intravesical treatment has been shown to be a risk factor associated with progression

** '''Mentioned in Campbell’s'''

*** '''Tumour architecture: papillary vs. sessile'''

*** '''Status of the remaining urothelium'''

== Genetics ~~of NMIBC~~ ==

== Genetics ==

* '''Tumor suppressor genes are mainly activated by''' allelic deletion of one allele followed by '''point mutations''' of the remaining allele

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*** High-risk p53 lesions have a 75% progression rate, compared with 25% in p53-negative lesions

*** The role of p53 for the prediction of tumor behavior requires prospective validation

== Prognosis ==

=== Recurrence ===

* '''Recurrence rate: ≈60-70%'''

** '''Primary theories for recurrent tumor formation (2):'''

**# '''Genetic field defect exists with multiple new tumors spontaneously arising within the bladder'''

**# '''Local reimplantation of tumor cells after tumor resection'''

**#* '''Tumor cell implantation immediately after resection may be responsible for many early recurrences, and this has been used to explain the observation that initial tumors are most commonly found on the floor and lower sidewalls of the bladder, whereas recurrences are often located near the dome as a result of “flotation”'''

* '''Risk factors (3):[https://pubmed.ncbi.nlm.nih.gov/33938798/ $$]'''

*# '''Prior recurrence rate''' (<1 year)

*# '''Number of tumours'''

*# '''Tumour size''' (>3 cm)

=== Progression ===

* '''Progression rates (defined by higher grade or stage): ≈20-30%'''

* '''Risk factors (3):[https://pubmed.ncbi.nlm.nih.gov/33938798/ $$]'''

*# '''Grade (most important)'''

*#* '''Grade more important than stage (unlike other cancers where stage is more important)'''

*#** '''High-grade tumors progress with similar frequency regardless of whether they are invasive (T1) or non-invasive (Ta)'''

*#** '''Stage Ta are usually LG; however, ≈7% of Ta disease is HG'''

*# '''Stage (second most important)'''

*#* '''TaLG: high recurrence rate (≈55%), but much lower stage progression rate ≈6%'''

*#* '''T1HG: high recurrence rate (≈45%) and high progression rate ≈17% [different numbers than Chapter 93]'''

*# '''CIS'''

*#* If CIS is treated only with TURBT,

*#** High risk of recurrence (as high as 90%)

*#** High risk (> 50%) for progressing to muscle-invasive disease.

*#* Even patients with a complete response to intravesical BCG will experience progression in 30% to 40% of cases on longitudinal follow-up

*#* Concomitant CIS is associated with significantly increased risk of disease progression and disease-specific mortality

'''Other risk factors'''

* '''Mentioned in [https://pubmed.ncbi.nlm.nih.gov/33938798/ 2021 CUA NMIBC Guidelines] (5):'''

*# '''Age > 70 yr'''

*# '''Extensive invasion of the lamina propria'''

*#* Extent of invasion of T1 tumours has been evaluated using two different criteria:

*## Micrometric: evaluates the millimetric extent of invasion into the lamina propria

*## Microanatomic: evaluates the level of invasion in relation to the muscularis mucosa (T1a – no muscularis mucosa invasion, T1b – invasion at the level of the muscularis mucosa and T1c – invasion beyond the muscularis mucosa)

*#*No single approach has been universally adopted

*# '''Lymphovascular invasion (LVI)'''

*#* '''Retrospective studies demonstrate that the presence of LVI is an independent factor for progression in patients with high-risk NMIBC'''.

*#** '''Use of LVI as a prognostic variable on transurethral resection (TUR) specimen requires prospective validation'''

*#* In NIMBC, LVI is associated with increased risk of recurrence and progression in BCG-treated patients with T1 NMIBC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4719750/ §]

*# '''Aggressive histological variants such as (3): micropapillary, plasmacytoid, and sarcomatoid'''

*#* See Bladder Cancer: Pathology & TNM Staging

*#* '''Associated with under-staging and early progression to muscle invasive disease'''

*# '''First assessment after TURBT'''

*#* Persistent disease at the first surveillance cystoscopy after induction intravesical treatment has been shown to be a risk factor associated with progression

* '''Mentioned in Campbell’s'''

** '''Tumour architecture: papillary vs. sessile'''

** '''Status of the remaining urothelium'''

=== Cancer-specific Survival ===

* 70-85% in high-grade NMIBC[https://pubmed.ncbi.nlm.nih.gov/38265030/], higher in low-grade disease

=== Estimating Prognosis ===

*[http://www.eortc.be/tools/bladdercalculator/ European Organization for Research and Treatment of Cancer (EORTC) Risk Tables]

**Provides individualized probability of recurrence and progression of NMIBC

**Developed from individual patient data from 2596 patients diagnosed with Ta/T1 tumours who were randomized in 7 EORTC trials.

**Estimates based on can be calculated based on (6):

**# Number of tumors

**# Tumor size

**# Prior recurrence rate

**# T category

**# Concomitant carcinoma in situ

**# Grade

** Note that the EORTC risk calculator likely overestimates the risk of recurrence and progression, as very few of the patients in these prospective trials received intravesical BCG

== Intravesical therapy ==

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==== Immediate instillation following TURBT ====

* '''~~Commonly used intravesical agents for single post-operative intravesical instillation of chemotherapy include~~ (5):'''

*# '''~~Gemcitabine~~''' (~~SWOG S0337§~~)

===== Mechanism of action =====

*# '''~~Mitomycin C~~ (~~MMC~~)'''

* '''Immediate instillation of intravesical chemotherapy may (2):'''

*# '''~~Doxorubicin~~'''

*# '''Reduce tumor cell implantation'''

*# '''~~Epirubicin~~'''

*# '''Have an ablative effect on small occult tumours/residual microscopic tumor at the site of TURBT'''

*# '''~~Pirarubicin~~'''

** '''All ~~equal efficacy as per CUA Guidelines~~'''

===== Indications =====

*** As per 11th Ed. Campbell’s, MMC appears to be the most effective adjuvant intravesical chemotherapeutic agent perioperatively, although epirubicin is used in Europe and direct comparative studies are lacking).

** '''~~Thiotepa has also been evaluated~~'''

====== 2024 AUA ======

* '''~~Reduces~~ risk ~~of tumour recurrence~~ (~~absolute risk reduction ≈12%~~)~~;~~ no benefit of chemotherapy on progression'''

** '''BCG ~~is the only agent~~ shown to delay or reduce high-grade tumor progression.''' No chemotherapy trials have achieved a significant reduction in progression

* '''Consider in''' '''(2):'''

** '''Meta-analysis evaluating intravesical chemotherapy on risk of recurrence'''

*# '''Low-risk (suspected or known) NMIBC'''

*** 13 studies including 2548 patients

*# '''Intermediate-risk (suspected or known) NMIBC'''

*** '''~~Intravesical~~ chemotherapy''' prolonged recurrence-free interval by 38% (HR: 0.62; 95% confidence interval [CI], 0.50-0.77; p<0.001; I(2): 69%), '''and early recurrences were 12% less likely in the intervention population (ARR: 0.12'''~~~~; 95% CI, -0.18 to -0.06; p<0.001, I(2): 0%). '''The number needed to treat to prevent one early recurrences was 8''' (95% CI, 6-17 patients).

*** High risk of bias present in 12 of 13 publications. Quality of evidence for recurrence-free interval was very low and low for early recurrences.

====== 2021 CUA ======

*** Immediate post-transurethral resection of bladder tumor intravesical chemotherapy prevents non-muscle-invasive bladder cancer recurrences: an updated meta-analysis on 2548 patients and quality-of-evidence review. Perlis et. al. Eur Urol. 2013 Sep;64(3):421-30.

* '''Recommended (2):'''

* ~~'''Mechanism of action'''~~

*# '''Intermediate-risk NMIBC'''

** '''~~The two primary theories for recurrent tumor formation~~:'''

*# '''Patients with ≤1 recurrence/year and European Organisation for Research and Treatment of Cancer (EORTC) recurrence score <5'''

*** ~~'''Genetic field defect exists~~ with ~~multiple new tumors spontaneously arising within the bladder'''~~

* '''Should be offered (1):'''

*** ~~'''Local reimplantation~~ of ~~tumor cells after tumor resection'''~~

** '''All patients with presumed low-risk NMIBC at TURBT'''

**** ~~'''Tumor cell implantation immediately after resection may be responsible for many early recurrences,~~ and ~~this has been used~~ to ~~explain the observation that initial tumors are most commonly found on the floor and lower sidewalls~~ of ~~the bladder, whereas recurrences are often located near the dome as a result of “flotation”'''~~

**** ~~'''Immediate~~ instillation of ~~intravesical chemotherapy may reducing~~ tumor ~~cell implantation~~'''

===== Contraindications =====

** '''~~Intravesical~~ chemotherapy ~~may also~~ have ~~an ablative effect on small occult tumours~~'''

# '''After extensive resection'''

* '''Particularly effective for the initial presentation of a (3):'''

# '''Suspected bladder perforation'''

*# '''Solitary'''

# '''Significant bleeding requiring bladder irrigation'''

*# '''Low-grade'''

#*'''Saline irrigation might be a consideration for patients with low- and intermediate risk NMIBC post-TURBT when intravesical chemotherapy is contraindicated (e.g., extensive bladder resection) or unavailable (2021 CUA NMIBC Guidelines)'''

*# '''Papillary tumor'''

===== Efficacy =====

*'''No benefit of immediate chemotherapy on progression or survival[https://pubmed.ncbi.nlm.nih.gov/38265030/]'''

**'''Only BCG has been shown to delay or reduce high-grade tumor progression.'''

***No chemotherapy trials have achieved a significant reduction in progression

*'''Reduces risk of tumour recurrence'''

**'''Number needed to treat to prevent 1 recurrence: 8 (absolute risk reduction ≈12%)'''

***'''Meta-analysis evaluating immediate intravesical chemotherapy on risk of recurrence'''

**** 13 studies including 2548 patients

**** '''Immediate intravesical chemotherapy''' prolonged recurrence-free interval by 38% (HR: 0.62; 95% confidence interval [CI], 0.50-0.77; p<0.001; I(2): 69%), '''and early recurrences were 12% less likely in the intervention population''' '''(ARR: 0.12'''; 95% CI, -0.18 to -0.06; p<0.001, I(2): 0%). '''The number needed to treat to prevent one early recurrences was 8''' (95% CI, 6-17 patients).

**** High risk of bias present in 12 of 13 publications. Quality of evidence for recurrence-free interval was very low and low for early recurrences.

**** Immediate post-transurethral resection of bladder tumor intravesical chemotherapy prevents non-muscle-invasive bladder cancer recurrences: an updated meta-analysis on 2548 patients and quality-of-evidence review. [https://pubmed.ncbi.nlm.nih.gov/29801011/ Perlis et. al.] Eur Urol. 2013 Sep;64(3):421-30.

*** '''SWOG 0337 (JAMA 2018)'''

**** Population: ≈400 patients with suspected low-grade NIMBC undergoing TURBT

**** Randomized to immediate post-TURBT intravesical instillation of gemcitabine vs saline

**** Outcomes

***** Primary: time to recurrence

***** Secondary: time to muscle invasion and death due to any cause

****Results

*****Time to recurrence: absolute risk reduction of 10-15% at 4 years

*****No significant difference in time to muscle invasion or death

****[https://pubmed.ncbi.nlm.nih.gov/29801011/ Messing, Edward M., et al. "Effect of intravesical instillation of gemcitabine vs saline immediately following resection of suspected low-grade non–muscle-invasive bladder cancer on tumor recurrence: SWOG S0337 randomized clinical trial." ''Jama'' 319.18 (2018): 1880-1888.]

*** '''Some have suggested that intravesical chemotherapy reduces overall cost of care by reducing the need for secondary resections. However, subsequent studies have shown that the tumors prevented are primarily smaller tumors that are often treated in the office or ambulatory surgery setting so the economic impact regarding recurrences remains controversial if recurrences are treated in any manner other than inpatient care'''

**'''Particularly effective for the initial presentation of a (3):'''

**# '''Solitary'''

**# '''Low-grade'''

**# '''Papillary tumor'''

** '''The incremental benefit in patients with recurrent or multiple tumors is limited.'''

** '''No benefit has been found in patients with high-grade disease.'''

** '''Given the number needed to treat of 8, some authors have suggested that intravesical chemotherapy reduces overall cost of care by reducing the need for secondary resections. However, subsequent studies have shown that the tumors prevented are primarily smaller tumors that are often treated in the office or ambulatory surgery setting so the economic impact regarding recurrences remains controversial if recurrences are treated in any manner other than inpatient care'''

* '''~~Indications~~'''

===== Commonly Used Agents (5): =====

** '''~~See 2016 AUA~~/~~2021 CUA NMBIC Guideline Notes~~'''

# '''Gemcitabine''' (SWOG 0337[https://pubmed.ncbi.nlm.nih.gov/29801011/ §])

* '''~~Contraindications~~'''

##Mechanism of action: inhibits DNA synthesis

*# '''~~After extensive resection~~'''

##Dose: 2g in 100mL[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5315602/]

*# '''~~Bladder perforation is suspected~~'''

# '''Mitomycin C (MMC)'''

*~~# '''Significant bleeding'''~~

##Mechanism of action: alkylating agent that inhibits DNA replication

*#'''~~Saline irrigation might be a consideration for patients with low-~~ and ~~intermediate risk NMIBC post-TURBT when intravesical chemotherapy is contraindicated (e~~.g.~~, extensive bladder resection) or unavailable (2021 CUA NMIBC Guidelines)~~'''

##Dose: 40g in 20-40mL

*'''~~Steps for Successful Perioperative Administration of Intravesical Chemotherapy~~'''

# '''Epirubicin'''

*# '''Include intent to administer perioperative chemotherapy (and agent) on actual operative schedule.'''

# '''Doxorubicin'''

*# '''Contact pharmacy before surgery to have medication available. A written prescription may be required.'''

# '''Pirarubicin'''

*# '''After resection, confirm absence of clinical perforation. Place three-way catheter into bladder while patient is still in operating room. Attach inflow port to saline infusion bag and clamp inflow.'''

* '''All equal efficacy as per CUA Guidelines'''

*# '''Administer chemotherapeutic agent through catheter outflow port in recovery room within 6 hours of operation, and clamp outflow tubing with hemostat to allow retention.'''

** As per 11th Ed. Campbell’s, MMC appears to be the most effective adjuvant intravesical chemotherapeutic agent perioperatively, although epirubicin is used in Europe and direct comparative studies are lacking).

*#* '''Efficacy of post-operative instillation significantly decreases if given beyond 24h'''

* '''Thiotepa and combination epirubicin and mitomycin C[https://pubmed.ncbi.nlm.nih.gov/36200115/] have also been evaluated'''

*# '''Give order for outflow tubing to be opened 1 hour after administration and for irrigation, to be opened to gravity drainage for next 30-60 minutes.'''

*# '''Remove Foley catheter and discard in biohazard container.'''

===== Steps for Successful Perioperative Administration of Intravesical Chemotherapy =====

*# '''Wear gloves'''

# '''Include intent to administer perioperative chemotherapy (and agent) on actual operative schedule.'''

* '''Methods to optimize MMC administration (may reduce recurrence rate further) (4):~~'''~~

# '''Contact pharmacy before surgery to have medication available. A written prescription may be required.'''

** '''Higher concentration (40mg in 20mL of sterile tumour)'''

# '''After resection, confirm absence of clinical perforation. Place three-way catheter into bladder while patient is still in operating room. Attach inflow port to saline infusion bag and clamp inflow.'''

** '''Urinary alkalinisation by using sodium bicarbonate to reduce drug degradation'''

# '''Administer chemotherapeutic agent through catheter outflow port in recovery room within 6 hours of operation, and clamp outflow tubing with hemostat to allow retention.'''

** '''Pre-treatment dehydration'''

#* '''Efficacy of post-operative instillation significantly decreases if given beyond 24h'''

** '''Complete bladder drainage prior to intravesical therapy'''

# '''Give order for outflow tubing to be opened 1 hour after administration and for irrigation, to be opened to gravity drainage for next 30-60 minutes.'''

* '''Adverse events§'''

# '''Remove Foley catheter and discard in biohazard container.'''

** '''MMC'''

# '''Wear gloves'''

*** '''Local irritative symptoms (most common complication)/chemical cystitis'''

*** '''Rash/Contact dermatitis (second most common complication)'''

===== Methods to optimize MMC administration (may reduce recurrence rate further) (4): =====

*** '''UTI'''

# '''Higher concentration (40mg in 20mL of sterile tumour)'''

*** '''Hematuria'''

# '''Urinary alkalinisation by using sodium bicarbonate to reduce drug degradation'''

*** '''Fever/chills'''

# '''Pre-treatment dehydration'''

*** '''Cutaneous hand/foot desquamation'''

# '''Complete bladder drainage prior to intravesical therapy'''

*** '''Decreased bladder capacity as a result of contractures'''

*** '''Calcified eschars'''

===== Adverse events'''[https://pubmed.ncbi.nlm.nih.gov/16925493/ §]''' =====

*** '''Added difficulty of subsequent cystectomy'''

* '''MMC'''

*** '''Serious sequelae and rare deaths have occurred, especially in patients with perforation during resection. Chemotherapy should be withheld in patients with extensive resection or when there is concern about perforation.'''

** '''Local irritative symptoms (most common complication)/chemical cystitis'''

** '''Thiotepa'''

** '''Rash/Contact dermatitis (second most common complication)'''

*** '''Local irritative symptoms'''

** '''UTI'''

*** '''Myelosuppresion'''

** '''Hematuria'''

**** '''The low molecular weight of thiotepa predisposes to systemic absorption and myelosuppression'''

** '''Fever/chills'''

** '''Cutaneous hand/foot desquamation'''

** '''Decreased bladder capacity as a result of contractures'''

** '''Calcified eschars'''

** '''Added difficulty of subsequent cystectomy'''

** '''Serious sequelae and rare deaths have occurred, especially in patients with perforation during resection.'''

***'''Chemotherapy should be withheld in patients with extensive resection or when there is concern about perforation.'''

**'''Given side effects of MMC, consider preferential use of gemcitabine which is better tolerated'''

* '''Thiotepa'''

** '''Local irritative symptoms'''

** '''Myelosuppresion'''

*** '''The low molecular weight of thiotepa predisposes to systemic absorption and myelosuppression'''

==== Induction and maintenance chemotherapy ====

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* In 1976, [https://pubmed.ncbi.nlm.nih.gov/820877/ Morales et al.] published the groundbreaking results of the first successful clinical trial of superficial bladder cancer treated with intravesical BCG

===== Mechanism of action~~: live~~ attenuated strain of mycobacterium bovis with anti-tumor activity ~~=====~~

===== Mechanism of action =====

* Mycobacterium bovis is closely related to mycobacterium tuberculosis

* '''Live attenuated strain of mycobacterium bovis with anti-tumor activity'''

*Mycobacterium bovis is closely related to mycobacterium tuberculosis

===== Efficacy =====

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===== Indications =====

* '''See~~''' '''~~2016 AUA/2021 CUA NMBIC Guideline Notes'''

* '''See [[CUA/AUA: Non-muscle Invasive Bladder Cancer (2021 CUA/2016 AUA))|2016 AUA/2021 CUA NMBIC]] Guideline Notes'''

* '''Campbell’s'''

** '''The AUA guidelines panel supported BCG as the preferred initial treatment option for CIS'''

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*# '''Immunosuppressed and immunocompromised patients'''

*#* '''Small series suggest this may not be an absolute contraindication'''

*# '''TURBT, immediately after resection due to risk of intravasation and septic death'''

*# '''TURBT, immediately after resection due to risk of intravasation and septic death'''

*# '''Incontinence (total)'''

*# '''Traumatic catheterization; ~~intravasation risk~~'''

*# '''Traumatic catheterization; intravasation risk'''

* '''Relative contraindications (4):'''

*# '''UTI (intravasation risk)'''

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*# '''Advanced age'''

* '''No or insufficient data on potential contraindications'''

** ~~'''~~Patients with prosthetic materials~~'''~~

** Patients with prosthetic materials

** ~~'''~~Ureteral reflux~~'''~~

** Ureteral reflux

** ~~'''~~Anti–tumor necrosis factor medications (theoretically predispose to BCG sepsis)~~'''~~

** Anti–tumor necrosis factor medications (theoretically predispose to BCG sepsis)

* '''Not contraindications'''

** '''Previous BCG vaccine'''

*** ~~'''~~A ~~[https://pubmed.ncbi.nlm.nih.gov/22674550/~~ retrospective cohort study] in 55 patients with high-risk non–muscle invasive bladder cancer that patients with a positive PPD had a significantly better recurrence-free survival than patients with a negative PPD skin test~~'''~~

*** A retrospective cohort study in 55 patients with high-risk non–muscle invasive bladder cancer that patients with a positive PPD had a significantly better recurrence-free survival than patients with a negative PPD skin test[https://pubmed.ncbi.nlm.nih.gov/22674550/]

** '''Personal history of tuberculosis'''

*** ~~'''~~Design: Population-based cohort study~~'''~~

*** Design: Population-based cohort study

*** ~~'''~~Population: 3915 patients from Taiwan with newely diagnosed bladder cancer and received adjuvant intravesical BCG therapy within 3 months after the surgery~~'''~~

*** Population: 3915 patients from Taiwan with newely diagnosed bladder cancer and received adjuvant intravesical BCG therapy within 3 months after the surgery

*** ~~'''~~Results:~~'''~~

*** Results:

**** ~~'''~~187 (4.8%) had been previously diagnosed with tuberculosis infection~~'''~~

**** 187 (4.8%) had been previously diagnosed with tuberculosis infection

**** ~~'''~~No significant difference in treatment efficacy or safety of intravesical BCG treatment~~'''~~

**** No significant difference in treatment efficacy or safety of intravesical BCG treatment

*** ~~'''~~[https://pubmed.ncbi.nlm.nih.gov/32641099/ Hsu, Che-Wei, et al.]"Can we treat bladder cancer with intravesical Bacillus Calmette-Guerin in patients with prior tuberculosis infection? A population-based cohort study." ''BMC urology'' 20.1 (2020): 1-7.~~'''~~

*** [https://pubmed.ncbi.nlm.nih.gov/32641099/ Hsu, Che-Wei, et al.]"Can we treat bladder cancer with intravesical Bacillus Calmette-Guerin in patients with prior tuberculosis infection? A population-based cohort study." ''BMC urology'' 20.1 (2020): 1-7.

*** ~~'''~~Campbell's 11th edition: relative contraindication, risk theorized but unknown~~'''~~

*** Campbell's 11th edition: relative contraindication, risk theorized but unknown

===== Dose =====

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===== Strain =====

* ~~'''~~Most commonly used strains in the US (2):~~'''~~

* Most commonly used strains in the US (2):

*# ~~'''~~BCG Tice~~'''~~

*# BCG Tice

*# ~~'''~~BCG Connaught~~'''~~

*# BCG Connaught

* '''Insufficient evidence to recommend a particular strain of BCG'''

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* '''Induction'''

** '''Two-hour intravesical instillation administered weekly over 6 weeks'''

** '''Treatments are typically begun 2-4 weeks after tumor resection, allowing time for re-epithelialization, which minimizes the potential for intravasation of live bacteria and systemic side effects~~'''~~

** '''Treatments are typically begun 2-4 weeks after tumor resection''', allowing time for re-epithelialization, which minimizes the potential for intravasation of live bacteria and systemic side effects

* '''Maintenance'''

** '''Two-hour intravesical instillation administered weekly over 3 weeks at 3, 6, 12, 18, 24, 30 and 36 months, counting from the beginning of induction therapy.'''

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===== Instillation =====

* '''A urinalysis is usually performed immediately before instillation to further confirm absence of infection or significant bleeding to decrease the likelihood of systemic uptake of BCG.'''

* ~~'''~~In the event of a traumatic catheterization, the treatment should be delayed for several days to 1 week~~'''~~

* In the event of a traumatic catheterization, the treatment should be delayed for several days to 1 week

* ~~'''~~After instillation, some clinicians have advocated that the patient turn from side to side to bathe the entire urothelium, but there is no scientific support for this practice. Fluid, diuretic, and caffeine restriction before instillation limits dilution of the agent by urine and facilitates adequate retention of the agent for 2 hours.~~'''~~

* After instillation, some clinicians have advocated that the patient turn from side to side to bathe the entire urothelium, but there is no scientific support for this practice. Fluid, diuretic, and caffeine restriction before instillation limits dilution of the agent by urine and facilitates adequate retention of the agent for 2 hours.

* ~~'''~~Patients are usually instructed to clean the toilet with bleach, although there is no demonstrable risk of close contact infection.~~'''~~

* Patients are usually instructed to clean the toilet with bleach, although there is no demonstrable risk of close contact infection.

===== Adverse events[https://pubmed.ncbi.nlm.nih.gov/30526332/] =====

* ~~'''~~Most commonly occur in the first year of therapy~~'''~~

* Most commonly occur in the first year of therapy

* ~~'''~~Serious toxicity occurs in ≈5% of patients~~'''~~

* Serious toxicity occurs in ≈5% of patients

* Pathogenesis

**Hypothesized mechanisms leading to adverse events (2):[https://pubmed.ncbi.nlm.nih.gov/11886488/]

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*'''Clinically classified as local vs. systemic'''

** '''Local'''

*** ~~'''~~Occurs in approximately 2/3 of patients~~'''~~

*** Occurs in approximately 2/3 of patients

*** ~~'''~~Result of BCG-contaminated urine~~'''~~

*** Result of BCG-contaminated urine

*** ~~'''~~Can occur anywhere along the genitourinary tract~~'''~~

*** Can occur anywhere along the genitourinary tract

*** '''Most common local adverse event: cystitis-like symptoms (hematuria, urgency, dysuria and increased urinary frequency)~~'''~~

*** '''Most common local adverse event: cystitis-like symptoms''' (hematuria, urgency, dysuria and increased urinary frequency)

**** ~~'''~~Can occur in up to 71% of patients~~'''~~

**** Can occur in up to 71% of patients

**** ~~'''~~Should be expected in the period immediately following BCG administration~~'''~~

**** Should be expected in the period immediately following BCG administration

**** ~~'''~~Urinalysis and urine cultures do not yield evidence of infection~~'''~~

**** Urinalysis and urine cultures do not yield evidence of infection

***** ~~'''~~Must be distinguished from bacterial cystitis, which should demonstrate evidence of infection at urinalysis and/or in urine cultures and requires treatment with antibiotics.~~'''~~

***** Must be distinguished from bacterial cystitis, which should demonstrate evidence of infection at urinalysis and/or in urine cultures and requires treatment with antibiotics.

**** ~~'''~~Symptoms usually last 1–2 days; however, the degree and duration of symptoms tend to increase with subsequent BCG instillations~~'''~~

**** Symptoms usually last 1–2 days; however, the degree and duration of symptoms tend to increase with subsequent BCG instillations

*** ~~'''~~Other local adverse events~~'''~~

*** Other local adverse events

**** ~~'''~~Bladder contracture~~'''~~

**** Bladder contracture

**** ~~'''~~Prostate: granulomatous prostatitis, prostate abscess~~'''~~

**** Prostate: granulomatous prostatitis, prostate abscess

***** '''Granulomatous prostatitis'''

****** ~~'''~~Common following intravesical BCG therapy~~'''~~

****** Common following intravesical BCG therapy

****** ~~'''~~May be due to reflux from the prostatic urethra to the prostatic ducts~~'''~~

****** May be due to reflux from the prostatic urethra to the prostatic ducts

****** ~~'''~~Majority of patients with GP are asymptomatic~~'''~~

****** Majority of patients with GP are asymptomatic

****** ~~'''~~Can result in abnormal digital rectal exam or abnormal PSA~~'''~~

****** Can result in abnormal digital rectal exam or abnormal PSA

****** '''Appearance on MRI can mimic prostate cancer'''

****** '''Management'''

******* '''Asymptomatic: no intervention; if patient on maintenance BCG, can be continued.'''

**** ~~'''~~Scrotum: granulomatous epididymo-orchitis, testicular abscess~~'''~~

**** Scrotum: granulomatous epididymo-orchitis, testicular abscess

**** ~~'''~~Upper urinary tract: pyelonephritis, renal abscess, renal granuloma, ureteral stricture~~'''~~

**** Upper urinary tract: pyelonephritis, renal abscess, renal granuloma, ureteral stricture

**** ~~'''~~Penis: balanitis~~'''~~

**** Penis: balanitis

** '''Systemic'''

*** ~~'''~~Occurs in approximately 1/3 of patients~~'''~~

*** Occurs in approximately 1/3 of patients

*** ~~'''~~Result of BCG dissemination to other sites via the bloodstream~~'''~~

*** Result of BCG dissemination to other sites via the bloodstream

*** '''Most common systemic adverse event: fever'''

**** ~~'''~~Indicates adequate immune activation and is associated with a more favorable anti-tumor response~~'''~~

**** Indicates adequate immune activation and is associated with a more favorable anti-tumor response

**** ~~'''~~Usually mild (<38.5ºC), lasting for less than 48 hours and accompanied by malaise and nausea.~~'''~~

**** Usually mild (<38.5ºC), lasting for less than 48 hours and accompanied by malaise and nausea.

**** ~~'''~~Persistent (> 48h) and high fever (> 38.5ºC) should prompt a complete workup for infection~~'''~~

**** Persistent (> 48h) and high fever (> 38.5ºC) should prompt a complete workup for infection

*** '''Most serious systemic adverse event: sepsis'''

**** '''Occurs in 1:15,000 patients'''

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** '''See [https://www.cua.org/system/files/Guideline-Files/7367_NMIBC%2520Guideline_Epub.pdf Table 6] from 2021 CUA NMIBC Guidelines'''

** '''Isoniazid, rifampin, and cycloserine are used for systemic BCG toxicity'''

** ~~'''~~Maneuvers to improve tolerability include reducing BCG dose and/or decreasing dwell time~~'''~~

** Maneuvers to improve tolerability include reducing BCG dose and/or decreasing dwell time

*** ~~'''~~The effect~~''' '''~~of BCG dose on toxicity is unclear~~'''~~

*** The effect of BCG dose on toxicity is unclear

==== Interferon (IFN) ====

* ~~'''~~Multiple anti-tumor properties~~'''~~

* Multiple anti-tumor properties

* '''More expensive as a solitary agent and less effective than BCG or intravesical chemotherapy in eradicating residual disease, preventing recurrence of papillary disease, and treating CIS; however, it can occasionally be effective in patients in whom BCG has failed~~'''~~

* '''More expensive as a solitary agent and less effective than BCG or intravesical chemotherapy''' in eradicating residual disease, preventing recurrence of papillary disease, and treating CIS; however, it can occasionally be effective in patients in whom BCG has failed

== Combination intravesical therapy ==

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*** '''Advantages:'''

**** '''Some activity in BCG failures, but may not be more effective than BCG alone'''

***** 2017 Cochrane Review

***** [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6464648/ 2017 Cochrane Review]

***** '''Studies: 5 RCTs'''

***** '''Population: 1231 patients with NMIBC''' (Ta and T1 superficial bladder cancer, with or without carcinoma in situ, treated with TUR)

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=== Management options in BCG unresponsive disease ===

* '''See [[CUA/AUA: Non-muscle Invasive Bladder Cancer (2021 CUA~~/2016~~ AUA))|~~2016~~ AUA/2021 CUA NMBIC]] Guideline Notes'''

* '''See [[CUA & AUA: Non-muscle Invasive Bladder Cancer (2021 CUA & 2024 AUA)|2024 AUA/2021 CUA NMBIC]] Guideline Notes'''

* '''Standard of care: radical cystectomy + lymph node dissection'''

** '''BCG-unresponsive with CIS or HG Ta: a second-line intravesical therapy might be considered before radical cystectomy'''

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*# '''Intravesical nadofaragene firadenovec'''

*# '''BCG plus N-803'''

*# '''Valrubicin[https://pubmed.ncbi.nlm.nih.gov/38265030/]'''

** Chemoradiation should not be recommended for patients with BCG-unresponsive CIS

* '''BCG-unresponsive who are unfit for or refuse to undergo radical cystectomy[https://pubmed.ncbi.nlm.nih.gov/33938798/]'''

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*# '''Sequential intravesical gemcitabine/docetaxel[https://pubmed.ncbi.nlm.nih.gov/31821066/ §] (induction plus maintenance)'''

*# '''Other combination intravesical therapy (e.g., sequential gemcitabine/MMC, BCG + interferon if available)'''

*# '''Single-agent intravesical therapy (MMC, epirubicin, docetaxel, gemcitabine)'''

*# '''Single-agent intravesical therapy (MMC, epirubicin, docetaxel, gemcitabine, valrubicin)'''

*#* For BCG-unresponsive patients undergoing intravesical chemotherapy, sequential combination of drugs is favoured instead of single-agent regimens

*#* See [https://www.cua.org/system/files/Guideline-Files/7367_NMIBC%2520Guideline_Epub.pdf Table 5] from 2021 CUA NMIBC Guidelines for dosing

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*#** '''>2 BCG induction courses is not recommended due to high failure rate'''

* '''Pembrolizumab~~'''~~

==== Pembrolizumab ====

** Systemic immunotherapy for NMIBC

* Systemic immunotherapy for NMIBC

** '''MOA: PD-1 checkpoint inhibitor'''

* '''MOA: PD-1 checkpoint inhibitor'''

** Dose: 200 mg IV q3weeks for up to 24 months

* Dose: 200 mg IV q3weeks for up to 24 months

** '''KEYNOTE-057 (Lancet Oncology 2021)'''

* '''KEYNOTE-057 (Lancet Oncology 2021)'''

*** Population: 96 patients with BCG-unresponsive CIS who were ineligible for or declined to undergo radical cystectomy

** Population: 96 patients with BCG-unresponsive CIS who were ineligible for or declined to undergo radical cystectomy

****BCG-unresponsive disease was defined as

***BCG-unresponsive disease was defined as

*****Stage progression at 3 months (or up to 4 weeks either side) despite adequate BCG induction therapy alone OR

****Stage progression at 3 months (or up to 4 weeks either side) despite adequate BCG induction therapy alone OR

*****Persistent high-risk non-muscle-invasive bladder cancer at 6 months (or up to 4 weeks either side) after adequate BCG therapy OR

****Persistent high-risk non-muscle-invasive bladder cancer at 6 months (or up to 4 weeks either side) after adequate BCG therapy OR

*****Recurrent high-risk non-muscle-invasive bladder cancer within 9 months after the last BCG instillation despite adequate BCG therapy.

****Recurrent high-risk non-muscle-invasive bladder cancer within 9 months after the last BCG instillation despite adequate BCG therapy.

*** '''Single arm study''': 200 mg of pembrolizumab IV q3 weeks for 24 months or until recurrence, progression or limiting toxicity

** '''Single arm study''': 200 mg of pembrolizumab IV q3 weeks for 24 months or until recurrence, progression or limiting toxicity

*** Primary outcome: clinical complete response rate (absence of high-risk non-muscle-invasive bladder cancer or progressive disease), assessed by cystoscopy and urine cytology approximately 3 months after the first dose of study drug.

** Primary outcome: clinical complete response rate (absence of high-risk non-muscle-invasive bladder cancer or progressive disease), assessed by cystoscopy and urine cytology approximately 3 months after the first dose of study drug.

*** Results

** Results

**** Median follow-up: 36.4 months

*** Median follow-up: 36.4 months

**** Complete response in 39 patients (41%) at 3 months

*** Complete response in 39 patients (41%) at 3 months

**** Median duration of response was 16.2 months

*** Median duration of response was 16.2 months

****Median duration of treatment was 4.2 months

***Median duration of treatment was 4.2 months

*****91% discontinued treatment; primary reasons for discontinuation were persistent disease and recurrent disease or stage progression to T1 disease

****91% discontinued treatment; primary reasons for discontinuation were persistent disease and recurrent disease or stage progression to T1 disease

****49% of initial responders and non-responders who discontinued pembrolizumab subsequently underwent radical cystectomy

***49% of initial responders and non-responders who discontinued pembrolizumab subsequently underwent radical cystectomy

**** Adverse events

*** Adverse events

*****Treatment-related adverse events in 66% of patients

****Treatment-related adverse events in 66% of patients

******13% of patients had grade 3 or 4 treatment-related adverse events

*****13% of patients had grade 3 or 4 treatment-related adverse events

******22% of patients had immune-related adverse events of any grade

*****22% of patients had immune-related adverse events of any grade

*****Most common treatment-related adverse events: hyponatremia (3%), arthralgia (2%)

****Most common treatment-related adverse events: hyponatremia (3%), arthralgia (2%)

*****Most common serious treatment-related adverse events: pneumonitis (3%), colitis (2%)

****Most common serious treatment-related adverse events: pneumonitis (3%), colitis (2%)

*****Treatment-related adverse events led to pembrolizumab interruption in 13% of patients

****Treatment-related adverse events led to pembrolizumab interruption in 13% of patients

*** [https://pubmed.ncbi.nlm.nih.gov/34051177/ Balar, Arjun V., et al.] "Pembrolizumab monotherapy for the treatment of high-risk non-muscle-invasive bladder cancer unresponsive to BCG (KEYNOTE-057): an open-label, single-arm, multicentre, phase 2 study." ''The Lancet Oncology'' (2021).

** [https://pubmed.ncbi.nlm.nih.gov/34051177/ Balar, Arjun V., et al.] "Pembrolizumab monotherapy for the treatment of high-risk non-muscle-invasive bladder cancer unresponsive to BCG (KEYNOTE-057): an open-label, single-arm, multicentre, phase 2 study." ''The Lancet Oncology'' (2021).

* ~~'''~~Nadofaragene firadenovec (Adstiladrin)~~'''~~

*In January 2020, received FDA approval for the treatment of patients with BCG-unresponsive, high-risk, NMIBC with CIS with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy

** '''MOA: a non-replicating adenovirus vector (rAd-INFa/Syn3) together with recombinant IFN-alpha2b. When given intravesically, the virus is transduced into bladder cells and the IFN-alpha2b gene is incorporated by the DNA. IFNalpha2b protein, which has antitumour activity, is then produced.~~'''~~

*** '''Single-arm trial'''

==== Nadofaragene firadenovec (Adstiladrin) ====

*** '''Population: 157 patients with BCG-unresponsive non-muscle-invasive bladder cancer~~'''~~

*** '''Results:~~'''~~

===== Mechanism of action =====

**** '''53% of patients with (with or without a high-grade Ta or T1 tumour) had a complete response within 3 months of the first dose and this response was maintained in 46% of 55 patients at 12 months.~~'''~~

* A non-replicating adenovirus vector (rAd-INFa/Syn3) together with recombinant IFN-alpha2b. When given intravesically, the virus is transduced into bladder cells and the IFN-alpha2b gene is incorporated by the DNA. IFNalpha2b protein, which has antitumour activity, is then produced.

*** '''Boorjian, Stephen A., et al. "Intravesical nadofaragene firadenovec gene therapy for BCG-unresponsive non-muscle-invasive bladder cancer: a single-arm, open-label, repeat-dose clinical trial." ''The Lancet Oncology'' 22.1 (2021): 107-117.~~'''~~

* ~~'''~~Oportuzumab monatox (Vicineum)~~'''~~

==== Efficacy ====

** '''MOA: specific antibody to Epithelial Cell Adhesion Molecule (EpCAM) fused to a Pseudomonas toxin that binds specifically to bladder cancer cells.~~'''~~

* '''Single-arm trial'''

* '''BCG plus N-803~~'''~~

** Population: 157 patients with BCG-unresponsive non-muscle-invasive bladder cancer

** '''MOA: N-803 is an IL-15 superagonist antibody cytokine fusion protein that can be co-administered intravesically with BCG to induce activation and proliferation of endogenous natural killer (NK) cells and CD8+ T-cells without inducing a T-reg response.~~'''~~

** Results:

*** 53% of patients with (with or without a high-grade Ta or T1 tumour) had a complete response within 3 months of the first dose and this response was maintained in 46% of 55 patients at 12 months.

** [https://pubmed.ncbi.nlm.nih.gov/33253641/ Boorjian, Stephen A., et al.] "Intravesical nadofaragene firadenovec gene therapy for BCG-unresponsive non-muscle-invasive bladder cancer: a single-arm, open-label, repeat-dose clinical trial." ''The Lancet Oncology'' 22.1 (2021): 107-117.

*In December 2022, received FDA approval for patients with high-risk BCG-unresponsive NMIBC with CIS with or without papillary tumors.

===== Technique =====

* Instilled every 3 months as a suspension

==== Oportuzumab monatox (Vicineum) ====

* MOA: specific antibody to Epithelial Cell Adhesion Molecule (EpCAM) fused to a Pseudomonas toxin that binds specifically to bladder cancer cells.

==== BCG plus N-803 ====

* MOA: N-803 is an IL-15 superagonist antibody cytokine fusion protein that can be co-administered intravesically with BCG to induce activation and proliferation of endogenous natural killer (NK) cells and CD8+ T-cells without inducing a T-reg response.

== Role of “timely” cystectomy ==

* '''See section on [[CUA & AUA: Non-muscle Invasive Bladder Cancer (2021 CUA & 2024 AUA)#Indications for Cystectomy in NMIBC|Indications for Cystectomy in NMIBC from AUA/CUA Guidelines]]'''

* Despite local therapy, many cases of high-grade NMIBC will progress to invasion and risk of cancer death

* '''The term “early” cystectomy is based on fact that they are performed before the traditional surgical indication of documented muscle invasion. A reasonable goal might be “timely” cystectomy for patients at risk.'''

** Cystectomy for CIS or persistent high-grade papillary disease after 2 courses of intravesical therapy, is the standard of care and should not be considered “early.”

* '''Indications:'''

** '''See 2016 AUA/2021 CUA NMBIC Guideline Notes'''

** '''See''' '''[[CUA/AUA: Non-muscle Invasive Bladder Cancer (2021 CUA/2016 AUA))|2016 AUA/2021 CUA NMBIC]] Guideline Notes'''

** Campbell’s:

*** High grade and invading deeply into lamina propria

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== Surveillance and Prevention ==

* '''See 2016 AUA/2021 CUA NMBIC Guideline Notes on recommendations for surveillance, which are based on risk-classification'''

* '''See''' '''[[CUA/AUA: Non-muscle Invasive Bladder Cancer (2021 CUA/2016 AUA))|2016 AUA/2021 CUA NMBIC]] Guideline Notes on recommendations for surveillance, which are based on risk-classification'''

* At 10 years, ≈30% of patients remain free of tumor progression or recurrence, so close follow-up is mandatory

* Most protocols include cystoscopy and urinary cytology every 3 months for 18-24 months after the initial diagnosis, then every 6 months for the following 2 years, and then annually, resetting the clock with each newly identified tumor

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* '''Extravesical surveillance'''

** '''Incidence of UTUC after bladder cancer: 3% (range 1.6% (low-risk) to 4.1% (high-risk))'''

** '''See 2016 AUA/2021 CUA NMBIC Guideline Notes on recommendations for upper-tract surveillance'''

** '''See''' '''[[CUA/AUA: Non-muscle Invasive Bladder Cancer (2021 CUA/2016 AUA))|2016 AUA/2021 CUA NMBIC]] Guideline Notes on recommendations for upper-tract surveillance'''

** Modality: CT and intravenous urography

* '''Prostatic urethral UC'''

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== Questions ==

See 2016 AUA/2021 CUA ~~NMIBC~~ Guideline Notes ~~Questions~~

'''See''' '''[[CUA/AUA: Non-muscle Invasive Bladder Cancer (2021 CUA/2016 AUA))|2016 AUA/2021 CUA NMBIC]] Guideline Notes'''

== Next Chapter: Muscle ~~invasive bladder cancer~~ ==

== Next Chapter: [[Muscle-Invasive Bladder Cancer]] ==

== Additional References ==

@@ Line 1: / Line 1: @@
 [[Category:Bladder Cancer]]
-'''<span style="color:#ff0000">See</span> [[CUA & AUA: Non-muscle Invasive Bladder Cancer (2021 CUA & 2020 AUA)|2016 AUA/2021 CUA NMBIC Guideline Notes]]'''
+<span style="color:#ff0000">'''See'''</span> '''[[CUA & AUA: Non-muscle Invasive Bladder Cancer (2021 CUA & 2024 AUA)|2024 AUA/2021 CUA NMBIC]] <span style="color:#ff0000">Guideline Notes</span>'''
 '''<span style="color:#ff0000">The notes below apply to urothelial carcinoma, not other histologies of bladder cancer such as pure squamous cell, adenocarcinoma, small cell, or other pure non-urothelial carcinomas of the bladder</span>'''
-== Diagnosis of NMIBC ==
+== Epidemiology ==
-* '''See [[Bladder Cancer: Diagnosis and Evaluation|Bladder Cancer: Diagnosis & Evaluation]]'''
+* '''<span style="color:#ff0000">≈75-80% of bladder cancer patients will present with NMIBC while ≈20-25% will present with MIBC and/or metastatic disease</span>'''
-* '''<span style="color:#ff0000">≈75-80% of patients will present with NMIBC and ≈20-25% will present with MIBC and/or metastatic disease</span>'''
+* '''<span style="color:#ff0000">Of patients with NMIBC, 70% are Ta, 20% are T1, and 10% are CIS</span>'''
-** '''<span style="color:#ff0000">Of patients with NMIBC, 70% are Ta, 20% are T1, and 10% are CIS</span>'''
+** Majority of Ta tumours are low-grade
-*** Majority of Ta tumours are low-grade
+** T1 tumours are almost always high-grade (2% of T1 tumours are classified low-grade)
-*** T1 tumours are almost always high-grade (2% of T1 tumours are classified low-grade)
+** Adjusted incidence of stage Ta has significantly increased, while stages Tis and T1 have slightly decreased
-*** Adjusted incidence of stage Ta has significantly increased, while stages Tis and T1 have slightly decreased
-== Prognosis of NMIBC ==
+== Diagnosis and Evaluation ==
-* '''<span style="color:#ff0000">Recurrence rate: ≈60-70%</span>'''
+* '''See [[Bladder Cancer: Diagnosis and Evaluation|Bladder Cancer: Diagnosis & Evaluation]]'''
-* '''<span style="color:#ff0000">Progression rate to a higher grade or stage: ≈20-30%</span>'''
-* '''<span style="color:#ff0000">Risk factors for recurrence and progression in NMIBC</span>''' (2015 CUA NMIBC Guidelines) '''<span style="color:#0000ffz">(6): </span><span style="color:#0000ff">Girish</span>''' (or other name with G) '''<span style="color:#0000ff">Sends Sexy Notes, Chocolates, and Roses</span>'''
-*# '''<span style="color:#0000ff">G</span><span style="color:#ff0000">rade (most important)</span>'''
-*#* '''<span style="color:#ff0000">Grade more important than stage</span>''' (unlike other cancers where stage is more important)
-*#** '''High-grade tumors progress with similar frequency regardless of whether they are invasive (T1) or non-invasive (Ta)'''
-*#** '''Stage Ta are usually LG; however, ≈7% of Ta disease is HG'''
-*# '''<span style="color:#0000ff">S</span><span style="color:#ff0000">tage (second most important)</span>'''
-*#* TaLG: high recurrence rate (≈55%), but much lower stage '''progression rate ≈6%'''
-*#* T1HG: high recurrence rate (≈45%) and high progression rate ≈17% [different numbers than Chapter 93]
-*# '''<span style="color:#0000ff">S</span><span style="color:#ff0000">ize</span> of tumour (>3 cm)'''
-*# '''<span style="color:#0000ff">N</span><span style="color:#ff0000">umber of tumours</span>'''
-*# '''<span style="color:#0000ff">R</span><span style="color:#ff0000">ecurrence rate prior</span>''' (>1 per year)
-*# '''<span style="color:#0000ff">C</span><span style="color:#ff0000">IS</span>'''
-*#* If CIS is treated only with TURBT,
-*#** High risk of recurrence (as high as 90%)
-*#** High risk (> 50%) for progressing to muscle-invasive disease.
-*#* Even patients with a complete response to intravesical BCG will experience progression in 30% to 40% of cases on longitudinal follow-up
-*#* Concomitant CIS is associated with significantly increased risk of disease progression and disease-specific mortality
-** '''2016 AUA NMIBC Guidelines:''' separated into recurrence vs. progression, same factors as CUA):
-*** '''Recurrence: prior recurrence rate, number of tumours, tumour size'''
-*** '''Progression: T-stage, grade, presence of CIS'''
-** Probability of recurrence and progression of NMIBC can be calculated based on these 6 factors with the [http://www.eortc.be/tools/bladdercalculator/ European Organization for Research and Treatment of Cancer (EORTC) risk tables].
-*** These tables were developed and based on individual patient data from 2596 patients diagnosed with Ta/T1 tumours who were randomized in 7 EORTC trials.
-*** Note that the EORTC risk calculator likely overestimates the risk of recurrence and progression, as very few of the patients in these prospective trials received intravesical BCG
-* '''<span style="color:#ff0000">Other risk factors</span>'''
-** '''Mentioned in [https://pubmed.ncbi.nlm.nih.gov/33938798/ 2021 CUA NMIBC Guidelines] (5):'''
-**# '''<span style="color:#ff0000">Age > 70 yr</span>'''
-**# '''<span style="color:#ff0000">Extensive invasion of the lamina propria</span>'''
-**#* Extent of invasion of T1 tumours has been evaluated using two different criteria:
-**## Micrometric: evaluates the millimetric extent of invasion into the lamina propria
-**## Microanatomic: evaluates the level of invasion in relation to the muscularis mucosa (T1a – no muscularis mucosa invasion, T1b – invasion at the level of the muscularis mucosa and T1c – invasion beyond the muscularis mucosa)
-**#*No single approach has been universally adopted
-**# '''<span style="color:#ff0000">Lymphovascular invasion (LVI)</span>'''
-**#* '''Retrospective studies demonstrate that the presence of LVI is an independent factor for progression in patients with high-risk NMIBC'''.
-**#** '''Use of LVI as a prognostic variable on transurethral resection (TUR) specimen requires prospective validation'''
-**#* In NIMBC, LVI is associated with increased risk of recurrence and progression in BCG-treated patients with T1 NMIBC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4719750/ §]
-**# '''<span style="color:#ff0000">Aggressive histological variants such as (3): micropapillary, plasmacytoid, and sarcomatoid</span>'''
-**#* See Bladder Cancer: Pathology & TNM Staging
-**#* '''<span style="color:#ff0000">Associated with under-staging and early progression to muscle invasive disease</span>'''
-**# '''<span style="color:#ff0000">First assessment after TURBT</span>'''
-**#* Persistent disease at the first surveillance cystoscopy after induction intravesical treatment has been shown to be a risk factor associated with progression
-** '''Mentioned in Campbell’s'''
-*** '''Tumour architecture: papillary vs. sessile'''
-*** '''Status of the remaining urothelium'''
-== Genetics of NMIBC ==
+== Genetics ==
 * '''Tumor suppressor genes are mainly activated by''' allelic deletion of one allele followed by '''point mutations''' of the remaining allele
@@ Line 74: / Line 29: @@
 *** High-risk p53 lesions have a 75% progression rate, compared with 25% in p53-negative lesions
 *** The role of p53 for the prediction of tumor behavior requires prospective validation
+== Prognosis ==
+=== Recurrence ===
+* '''<span style="color:#ff0000">Recurrence rate: ≈60-70%</span>'''
+** '''Primary theories for recurrent tumor formation (2):'''
+**# '''Genetic field defect exists with multiple new tumors spontaneously arising within the bladder'''
+**# '''Local reimplantation of tumor cells after tumor resection'''
+**#* '''Tumor cell implantation immediately after resection may be responsible for many early recurrences, and this has been used to explain the observation that initial tumors are most commonly found on the floor and lower sidewalls of the bladder, whereas recurrences are often located near the dome as a result of “flotation”'''
+* <span style="color:#ff0000">'''Risk factors (3):[https://pubmed.ncbi.nlm.nih.gov/33938798/ $$]'''</span>
+*# <span style="color:#ff0000">'''Prior recurrence rate'''</span> (<1 year)
+*# <span style="color:#ff0000">'''Number of tumours'''</span>
+*# <span style="color:#ff0000">'''Tumour size'''</span> (>3 cm)
+=== Progression ===
+* '''<span style="color:#ff0000">Progression rates (defined by higher grade or stage): ≈20-30%</span>'''
+* '''<span style="color:#ff0000">Risk factors (3):[https://pubmed.ncbi.nlm.nih.gov/33938798/ $$]</span>'''
+*# '''<span style="color:#ff0000">Grade (most important)</span>'''
+*#* '''<span style="color:#ff0000">Grade more important than stage (unlike other cancers where stage is more important)</span>'''
+*#** '''<span style="color:#ff0000">High-grade tumors progress with similar frequency regardless of whether they are invasive (T1) or non-invasive (Ta)</span>'''
+*#** '''<span style="color:#ff0000">Stage Ta are usually LG; however, ≈7% of Ta disease is HG</span>'''
+*# '''<span style="color:#ff0000">Stage (second most important)</span>'''
+*#* '''<span style="color:#ff0000">TaLG: high recurrence rate (≈55%), but much lower stage progression rate ≈6%</span>'''
+*#* '''<span style="color:#ff0000">T1HG: high recurrence rate (≈45%) and high progression rate ≈17% [different numbers than Chapter 93]</span>'''
+*# '''<span style="color:#ff0000">CIS</span>'''
+*#* If CIS is treated only with TURBT,
+*#** High risk of recurrence (as high as 90%)
+*#** High risk (> 50%) for progressing to muscle-invasive disease.
+*#* Even patients with a complete response to intravesical BCG will experience progression in 30% to 40% of cases on longitudinal follow-up
+*#* Concomitant CIS is associated with significantly increased risk of disease progression and disease-specific mortality
+'''<span style="color:#ff0000">Other risk factors</span>'''
+* '''Mentioned in [https://pubmed.ncbi.nlm.nih.gov/33938798/ 2021 CUA NMIBC Guidelines] (5):'''
+*# '''<span style="color:#ff0000">Age > 70 yr</span>'''
+*# '''<span style="color:#ff0000">Extensive invasion of the lamina propria</span>'''
+*#* Extent of invasion of T1 tumours has been evaluated using two different criteria:
+*## Micrometric: evaluates the millimetric extent of invasion into the lamina propria
+*## Microanatomic: evaluates the level of invasion in relation to the muscularis mucosa (T1a – no muscularis mucosa invasion, T1b – invasion at the level of the muscularis mucosa and T1c – invasion beyond the muscularis mucosa)
+*#*No single approach has been universally adopted
+*# '''<span style="color:#ff0000">Lymphovascular invasion (LVI)</span>'''
+*#* '''Retrospective studies demonstrate that the presence of LVI is an independent factor for progression in patients with high-risk NMIBC'''.
+*#** '''Use of LVI as a prognostic variable on transurethral resection (TUR) specimen requires prospective validation'''
+*#* In NIMBC, LVI is associated with increased risk of recurrence and progression in BCG-treated patients with T1 NMIBC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4719750/ §]
+*# '''<span style="color:#ff0000">Aggressive histological variants such as (3): micropapillary, plasmacytoid, and sarcomatoid</span>'''
+*#* See Bladder Cancer: Pathology & TNM Staging
+*#* '''<span style="color:#ff0000">Associated with under-staging and early progression to muscle invasive disease</span>'''
+*# '''<span style="color:#ff0000">First assessment after TURBT</span>'''
+*#* Persistent disease at the first surveillance cystoscopy after induction intravesical treatment has been shown to be a risk factor associated with progression
+* '''Mentioned in Campbell’s'''
+** '''Tumour architecture: papillary vs. sessile'''
+** '''Status of the remaining urothelium'''
+=== Cancer-specific Survival ===
+* 70-85% in high-grade NMIBC[https://pubmed.ncbi.nlm.nih.gov/38265030/], higher in low-grade disease
+=== Estimating Prognosis ===
+*[http://www.eortc.be/tools/bladdercalculator/ European Organization for Research and Treatment of Cancer (EORTC) Risk Tables]
+**Provides individualized probability of recurrence and progression of NMIBC
+**Developed from individual patient data from 2596 patients diagnosed with Ta/T1 tumours who were randomized in 7 EORTC trials.
+**Estimates based on can be calculated based on (6):
+**# Number of tumors
+**# Tumor size
+**# Prior recurrence rate
+**# T category
+**# Concomitant carcinoma in situ
+**# Grade
+** Note that the EORTC risk calculator likely overestimates the risk of recurrence and progression, as very few of the patients in these prospective trials received intravesical BCG
 == Intravesical therapy ==
@@ Line 83: / Line 105: @@
 ==== Immediate instillation following TURBT ====
-* '''<span style="color:#ff0000">Commonly used intravesical agents for single post-operative intravesical instillation of chemotherapy include (5):</span>'''
-*# '''<span style="color:#ff0000">Gemcitabine</span>''' (SWOG S0337§)
+===== Mechanism of action =====
-*# '''<span style="color:#ff0000">Mitomycin C (MMC)</span>'''
+* '''Immediate instillation of intravesical chemotherapy may (2):'''
-*# '''<span style="color:#ff0000">Doxorubicin</span>'''
+*# '''Reduce tumor cell implantation'''
-*# '''<span style="color:#ff0000">Epirubicin</span>'''
+*# '''Have an ablative effect on small occult tumours/residual microscopic tumor at the site of TURBT'''
-*# '''<span style="color:#ff0000">Pirarubicin</span>'''
-** '''All equal efficacy as per CUA Guidelines'''
+===== Indications =====
-*** As per 11th Ed. Campbell’s, MMC appears to be the most effective adjuvant intravesical chemotherapeutic agent perioperatively, although epirubicin is used in Europe and direct comparative studies are lacking).
-** '''Thiotepa has also been evaluated'''
+====== 2024 AUA ======
-* '''<span style="color:#ff0000">Reduces risk of tumour recurrence (absolute risk reduction ≈12%)</span>; <span style="color:#ff0000">no benefit of chemotherapy on progression</span>'''
-** '''BCG is the only agent shown to delay or reduce high-grade tumor progression.''' No chemotherapy trials have achieved a significant reduction in progression
+* '''<span style="color:#ff0000">Consider in</span>''' '''<span style="color:#ff0000">(2):</span>'''
-** '''<span style="color:#ff00ff">Meta-analysis evaluating intravesical chemotherapy on risk of recurrence</span>'''
+*# '''<span style="color:#ff0000">Low-risk (suspected or known) NMIBC</span>'''
-*** 13 studies including 2548 patients
+*# '''<span style="color:#ff0000">Intermediate-risk (suspected or known) NMIBC</span>'''
-*** '''<span style="color:#ff0000">Intravesical chemotherapy</span>''' prolonged recurrence-free interval by 38% (HR: 0.62; 95% confidence interval [CI], 0.50-0.77; p<0.001; I(2): 69%), '''<span style="color:#ff0000">and early recurrences were 12% less likely in the intervention population (ARR: 0.12'''</span>; 95% CI, -0.18 to -0.06; p<0.001, I(2): 0%). '''The number needed to treat to prevent one early recurrences was 8''' (95% CI, 6-17 patients).
-*** High risk of bias present in 12 of 13 publications. Quality of evidence for recurrence-free interval was very low and low for early recurrences.
+====== 2021 CUA ======
-*** Immediate post-transurethral resection of bladder tumor intravesical chemotherapy prevents non-muscle-invasive bladder cancer recurrences: an updated meta-analysis on 2548 patients and quality-of-evidence review. Perlis et. al. Eur Urol. 2013 Sep;64(3):421-30.
+* '''<span style="color:#ff0000">Recommended (2):</span>'''
-* '''Mechanism of action'''
+*# '''<span style="color:#ff0000">Intermediate-risk NMIBC</span>'''
-** '''The two primary theories for recurrent tumor formation:'''
+*# '''<span style="color:#ff0000">Patients with ≤1 recurrence/year and European Organisation for Research and Treatment of Cancer (EORTC) recurrence score <5</span>'''
-*** '''Genetic field defect exists with multiple new tumors spontaneously arising within the bladder'''
+* '''<span style="color:#ff0000">Should be offered (1):</span>'''
-*** '''Local reimplantation of tumor cells after tumor resection'''
+** '''<span style="color:#ff0000">All patients with presumed low-risk NMIBC at TURBT</span>'''
-**** '''Tumor cell implantation immediately after resection may be responsible for many early recurrences, and this has been used to explain the observation that initial tumors are most commonly found on the floor and lower sidewalls of the bladder, whereas recurrences are often located near the dome as a result of “flotation”'''
-**** '''Immediate instillation of intravesical chemotherapy may reducing tumor cell implantation'''
+===== Contraindications =====
-** '''Intravesical chemotherapy may also have an ablative effect on small occult tumours'''
+# '''<span style="color:#ff0000">After extensive resection'''
-* '''<span style="color:#ff0000">Particularly effective for the initial presentation of a (3):</span>'''
+# '''<span style="color:#ff0000">Suspected bladder perforation'''
-*# '''<span style="color:#ff0000">Solitary</span>'''
+# '''<span style="color:#ff0000">Significant bleeding requiring bladder irrigation'''
-*# '''<span style="color:#ff0000">Low-grade</span>'''
+#*'''Saline irrigation might be a consideration for patients with low- and intermediate risk NMIBC post-TURBT when intravesical chemotherapy is contraindicated (e.g., extensive bladder resection) or unavailable (2021 CUA NMIBC Guidelines)'''
-*# '''<span style="color:#ff0000">Papillary tumor</span>'''
+===== Efficacy =====
+*'''<span style="color:#ff0000">No benefit of immediate chemotherapy on progression or survival[https://pubmed.ncbi.nlm.nih.gov/38265030/]</span>'''
+**'''Only BCG has been shown to delay or reduce high-grade tumor progression.'''
+***No chemotherapy trials have achieved a significant reduction in progression
+*'''<span style="color:#ff0000">Reduces risk of tumour recurrence</span>'''
+**'''<span style="color:#ff0000">Number needed to treat to prevent 1 recurrence: 8 (absolute risk reduction ≈12%)'''
+***'''<span style="color:#ff00ff">Meta-analysis evaluating immediate intravesical chemotherapy on risk of recurrence</span>'''
+**** 13 studies including 2548 patients
+**** '''<span style="color:#ff0000">Immediate intravesical chemotherapy</span>''' prolonged recurrence-free interval by 38% (HR: 0.62; 95% confidence interval [CI], 0.50-0.77; p<0.001; I(2): 69%), '''<span style="color:#ff0000">and early recurrences were 12% less likely in the intervention population''' </span>'''<span style="color:#ff0000">(ARR: 0.12'''; 95% CI, -0.18 to -0.06; p<0.001, I(2): 0%). '''The number needed to treat to prevent one early recurrences was 8''' (95% CI, 6-17 patients).
+**** High risk of bias present in 12 of 13 publications. Quality of evidence for recurrence-free interval was very low and low for early recurrences.
+**** Immediate post-transurethral resection of bladder tumor intravesical chemotherapy prevents non-muscle-invasive bladder cancer recurrences: an updated meta-analysis on 2548 patients and quality-of-evidence review. [https://pubmed.ncbi.nlm.nih.gov/29801011/ Perlis et. al.] Eur Urol. 2013 Sep;64(3):421-30.
+*** '''<span style="color:#ff00ff">SWOG 0337 (JAMA 2018)'''
+**** Population: ≈400 patients with suspected low-grade NIMBC undergoing TURBT
+**** Randomized to immediate post-TURBT intravesical instillation of gemcitabine vs saline
+**** Outcomes
+***** Primary: time to recurrence
+***** Secondary: time to muscle invasion and death due to any cause
+****Results
+*****Time to recurrence: absolute risk reduction of 10-15% at 4 years
+*****No significant difference in time to muscle invasion or death
+****[https://pubmed.ncbi.nlm.nih.gov/29801011/ Messing, Edward M., et al. "Effect of intravesical instillation of gemcitabine vs saline immediately following resection of suspected low-grade non–muscle-invasive bladder cancer on tumor recurrence: SWOG S0337 randomized clinical trial." ''Jama'' 319.18 (2018): 1880-1888.]
+*** '''Some have suggested that intravesical chemotherapy reduces overall cost of care by reducing the need for secondary resections. However, subsequent studies have shown that the tumors prevented are primarily smaller tumors that are often treated in the office or ambulatory surgery setting so the economic impact regarding recurrences remains controversial if recurrences are treated in any manner other than inpatient care'''
+**'''<span style="color:#ff0000">Particularly effective for the initial presentation of a (3):</span>'''
+**# '''<span style="color:#ff0000">Solitary</span>'''
+**# '''<span style="color:#ff0000">Low-grade</span>'''
+**# '''<span style="color:#ff0000">Papillary tumor</span>'''
 ** '''<span style="color:#ff0000">The incremental benefit in patients with recurrent or multiple tumors is limited.</span>'''
 ** '''<span style="color:#ff0000">No benefit has been found in patients with high-grade disease.</span>'''
-** '''Given the number needed to treat of 8, some authors have suggested that intravesical chemotherapy reduces overall cost of care by reducing the need for secondary resections. However, subsequent studies have shown that the tumors prevented are primarily smaller tumors that are often treated in the office or ambulatory surgery setting so the economic impact regarding recurrences remains controversial if recurrences are treated in any manner other than inpatient care'''
-* '''<span style="color:#ff0000">Indications</span>'''
+===== Commonly Used Agents (5): =====
-** '''See 2016 AUA/2021 CUA NMBIC Guideline Notes'''
+# '''<span style="color:#ff0000">Gemcitabine</span>''' (SWOG 0337[https://pubmed.ncbi.nlm.nih.gov/29801011/ §])
-* '''Contraindications'''
+##Mechanism of action: inhibits DNA synthesis
-*# '''After extensive resection'''
+##Dose: 2g in 100mL[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5315602/]
-*# '''Bladder perforation is suspected'''
+# '''<span style="color:#ff0000">Mitomycin C (MMC)</span>'''
-*# '''Significant bleeding'''
+##Mechanism of action: alkylating agent that inhibits DNA replication
-*#'''Saline irrigation might be a consideration for patients with low- and intermediate risk NMIBC post-TURBT when intravesical chemotherapy is contraindicated (e.g., extensive bladder resection) or unavailable (2021 CUA NMIBC Guidelines)'''
+##Dose: 40g in 20-40mL
-*'''<span style="color:#ff0000">Steps for Successful Perioperative Administration of Intravesical Chemotherapy</span>'''
+# '''<span style="color:#ff0000">Epirubicin</span>'''
-*# '''Include intent to administer perioperative chemotherapy (and agent) on actual operative schedule.'''
+# '''<span style="color:#ff0000">Doxorubicin</span>'''
-*# '''Contact pharmacy before surgery to have medication available. A written prescription may be required.'''
+# '''<span style="color:#ff0000">Pirarubicin</span>'''
-*# '''After resection, confirm absence of clinical perforation. Place three-way catheter into bladder while patient is still in operating room. Attach inflow port to saline infusion bag and clamp inflow.'''
+* '''All equal efficacy as per CUA Guidelines'''
-*# '''Administer chemotherapeutic agent through catheter outflow port in recovery room <span style="color:#ff0000">within 6 hours of operation,</span> and clamp outflow tubing with hemostat to allow retention.'''
+** As per 11th Ed. Campbell’s, MMC appears to be the most effective adjuvant intravesical chemotherapeutic agent perioperatively, although epirubicin is used in Europe and direct comparative studies are lacking).
-*#* '''<span style="color:#ff0000">Efficacy of post-operative instillation significantly decreases if given beyond 24h</span>'''
+* '''Thiotepa and combination epirubicin and mitomycin C[https://pubmed.ncbi.nlm.nih.gov/36200115/] have also been evaluated'''
-*# '''Give order for <span style="color:#ff0000">outflow tubing to be opened 1 hour after administration</span> and for irrigation, to be opened to gravity drainage for next 30-60 minutes.'''
-*# '''Remove Foley catheter and discard in biohazard container.'''
+===== Steps for Successful Perioperative Administration of Intravesical Chemotherapy =====
-*# '''Wear gloves'''
+# '''Include intent to administer perioperative chemotherapy (and agent) on actual operative schedule.'''
-* '''<span style="color:#ff0000">Methods to optimize MMC administration</span> (may reduce recurrence rate further) <span style="color:#ff0000">(4):'''
+# '''Contact pharmacy before surgery to have medication available. A written prescription may be required.'''
-** '''<span style="color:#ff0000">Higher concentration (40mg in 20mL of sterile tumour)</span>'''
+# '''After resection, confirm absence of clinical perforation. Place three-way catheter into bladder while patient is still in operating room. Attach inflow port to saline infusion bag and clamp inflow.'''
-** '''<span style="color:#ff0000">Urinary alkalinisation</span> by using sodium bicarbonate to reduce drug degradation'''
+# '''Administer chemotherapeutic agent through catheter outflow port in recovery room <span style="color:#ff0000">within 6 hours of operation,</span> and clamp outflow tubing with hemostat to allow retention.'''
-** '''<span style="color:#ff0000">Pre-treatment dehydration</span>'''
+#* '''<span style="color:#ff0000">Efficacy of post-operative instillation significantly decreases if given beyond 24h</span>'''
-** '''<span style="color:#ff0000">Complete bladder drainage prior to intravesical therapy</span>'''
+# '''Give order for <span style="color:#ff0000">outflow tubing to be opened 1 hour after administration</span> and for irrigation, to be opened to gravity drainage for next 30-60 minutes.'''
-* '''<span style="color:#ff0000">Adverse events</span>§'''
+# '''Remove Foley catheter and discard in biohazard container.'''
-** '''<span style="color:#ff0000">MMC</span>'''
+# '''Wear gloves'''
-*** '''<span style="color:#ff0000">Local irritative symptoms (most common complication)</span>/chemical cystitis'''
-*** '''<span style="color:#ff0000">Rash/Contact dermatitis (second most common complication)</span>'''
+===== <span style="color:#ff0000">Methods to optimize MMC administration</span> (may reduce recurrence rate further) <span style="color:#ff0000">(4): =====
-*** '''<span style="color:#ff0000">UTI</span>'''
+# '''<span style="color:#ff0000">Higher concentration (40mg in 20mL of sterile tumour)</span>'''
-*** '''<span style="color:#ff0000">Hematuria</span>'''
+# '''<span style="color:#ff0000">Urinary alkalinisation</span> by using sodium bicarbonate to reduce drug degradation'''
-*** '''<span style="color:#ff0000">Fever/chills</span>'''
+# '''<span style="color:#ff0000">Pre-treatment dehydration</span>'''
-*** '''<span style="color:#ff0000">Cutaneous hand/foot desquamation</span>'''
+# '''<span style="color:#ff0000">Complete bladder drainage prior to intravesical therapy</span>'''
-*** '''<span style="color:#ff0000">Decreased bladder capacity as a result of contractures</span>'''
-*** '''<span style="color:#ff0000">Calcified eschars</span>'''
+===== <span style="color:#ff0000">Adverse events</span>'''[https://pubmed.ncbi.nlm.nih.gov/16925493/ §]''' =====
-*** '''<span style="color:#ff0000">Added difficulty of subsequent cystectomy</span>'''
+* '''<span style="color:#ff0000">MMC</span>'''
-*** '''Serious sequelae and rare deaths have occurred, especially in patients with perforation during resection. <span style="color:#ff0000">Chemotherapy should be withheld in patients with extensive resection or when there is concern about perforation.</span>'''
+** '''<span style="color:#ff0000">Local irritative symptoms (most common complication)</span>/chemical cystitis'''
-** '''<span style="color:#ff0000">Thiotepa</span>'''
+** '''<span style="color:#ff0000">Rash/Contact dermatitis (second most common complication)</span>'''
-*** '''<span style="color:#ff0000">Local irritative symptoms</span>'''
+** '''<span style="color:#ff0000">UTI</span>'''
-*** '''<span style="color:#ff0000">Myelosuppresion</span>'''
+** '''<span style="color:#ff0000">Hematuria</span>'''
-**** '''The low molecular weight of thiotepa predisposes to systemic absorption and myelosuppression'''
+** '''<span style="color:#ff0000">Fever/chills</span>'''
+** '''<span style="color:#ff0000">Cutaneous hand/foot desquamation</span>'''
+** '''<span style="color:#ff0000">Decreased bladder capacity as a result of contractures</span>'''
+** '''<span style="color:#ff0000">Calcified eschars</span>'''
+** '''<span style="color:#ff0000">Added difficulty of subsequent cystectomy</span>'''
+** '''Serious sequelae and rare deaths have occurred, especially in patients with perforation during resection.'''
+***'''<span style="color:#ff0000">Chemotherapy should be withheld in patients with extensive resection or when there is concern about perforation.</span>'''
+**'''Given side effects of MMC, consider preferential use of gemcitabine which is better tolerated'''
+* '''<span style="color:#ff0000">Thiotepa</span>'''
+** '''<span style="color:#ff0000">Local irritative symptoms</span>'''
+** '''<span style="color:#ff0000">Myelosuppresion</span>'''
+*** '''The low molecular weight of thiotepa predisposes to systemic absorption and myelosuppression'''
 ==== Induction and maintenance chemotherapy ====
@@ Line 168: / Line 227: @@
 * In 1976, [https://pubmed.ncbi.nlm.nih.gov/820877/ Morales et al.] published the groundbreaking results of the first successful clinical trial of superficial bladder cancer treated with intravesical BCG
-===== Mechanism of action: live attenuated strain of mycobacterium bovis with anti-tumor activity =====
+===== Mechanism of action =====
-* Mycobacterium bovis is closely related to mycobacterium tuberculosis
+* '''Live attenuated strain of mycobacterium bovis with anti-tumor activity'''
+*Mycobacterium bovis is closely related to mycobacterium tuberculosis
 ===== Efficacy =====
@@ Line 203: / Line 263: @@
 ===== Indications =====
-* '''See''' '''2016 AUA/2021 CUA NMBIC Guideline Notes'''
+* '''<span style="color:#ff0000">See</span> [[CUA/AUA: Non-muscle Invasive Bladder Cancer (2021 CUA/2016 AUA))|2016 AUA/2021 CUA NMBIC]] <span style="color:#ff0000">Guideline Notes</span>'''
 * '''Campbell’s'''
 ** '''The AUA guidelines panel supported BCG as the preferred initial treatment option for CIS'''
@@ Line 232: / Line 292: @@
 *# '''<span style="color:#0000ff">I</span><span style="color:#ff0000">mmunosuppressed and immunocompromised patients</span>'''
 *#* '''Small series suggest this may not be an absolute contraindication'''
-*# '''<span style="color:#0000ff">T<span style="color:#ff0000">URBT, immediately after resection</span> due to risk of intravasation and septic death'''
+*# '''<span style="color:#0000ff">T</span><span style="color:#ff0000">URBT, immediately after resection</span> due to risk of intravasation and septic death'''
 *# '''<span style="color:#0000ff">I</span><span style="color:#ff0000">ncontinence (total)</span>'''
-*# '''<span style="color:#0000ff">T</span><span style="color:#ff0000">raumatic catheterization; intravasation risk</span>'''
+*# '''<span style="color:#0000ff">T</span><span style="color:#ff0000">raumatic catheterization;</span> intravasation risk'''
 * '''<span style="color:#ff0000">Relative contraindications (4):</span>'''
 *# '''<span style="color:#ff0000">UTI (intravasation risk)</span>'''
@@ Line 241: / Line 301: @@
 *# '''<span style="color:#ff0000">Advanced age</span>'''
 * '''No or insufficient data on potential contraindications'''
-** '''Patients with prosthetic materials'''
+** Patients with prosthetic materials
-** '''Ureteral reflux'''
+** Ureteral reflux
-** '''Anti–tumor necrosis factor medications (theoretically predispose to BCG sepsis)'''
+** Anti–tumor necrosis factor medications (theoretically predispose to BCG sepsis)
 * '''Not contraindications'''
 ** '''Previous BCG vaccine'''
-*** '''A [https://pubmed.ncbi.nlm.nih.gov/22674550/ retrospective cohort study] in 55 patients with high-risk non–muscle invasive bladder cancer that patients with a positive PPD had a significantly better recurrence-free survival than patients with a negative PPD skin test'''
+*** A retrospective cohort study in 55 patients with high-risk non–muscle invasive bladder cancer that patients with a positive PPD had a significantly better recurrence-free survival than patients with a negative PPD skin test[https://pubmed.ncbi.nlm.nih.gov/22674550/]
 ** '''Personal history of tuberculosis'''
-*** '''Design: Population-based cohort study'''
+*** Design: Population-based cohort study
-*** '''Population: 3915 patients from Taiwan with newely diagnosed bladder cancer and received adjuvant intravesical BCG therapy within 3 months after the surgery'''
+*** Population: 3915 patients from Taiwan with newely diagnosed bladder cancer and received adjuvant intravesical BCG therapy within 3 months after the surgery
-*** '''Results:'''
+*** Results:
-**** '''187 (4.8%) had been previously diagnosed with tuberculosis infection'''
+**** 187 (4.8%) had been previously diagnosed with tuberculosis infection
-**** '''No significant difference in treatment efficacy or safety of intravesical BCG treatment'''
+**** No significant difference in treatment efficacy or safety of intravesical BCG treatment
-*** '''[https://pubmed.ncbi.nlm.nih.gov/32641099/ Hsu, Che-Wei, et al.]"Can we treat bladder cancer with intravesical Bacillus Calmette-Guerin in patients with prior tuberculosis infection? A population-based cohort study." ''BMC urology'' 20.1 (2020): 1-7.'''
+*** [https://pubmed.ncbi.nlm.nih.gov/32641099/ Hsu, Che-Wei, et al.]"Can we treat bladder cancer with intravesical Bacillus Calmette-Guerin in patients with prior tuberculosis infection? A population-based cohort study." ''BMC urology'' 20.1 (2020): 1-7.
-*** '''Campbell's 11th edition: relative contraindication, risk theorized but unknown'''
+*** Campbell's 11th edition: relative contraindication, risk theorized but unknown
 ===== Dose =====
@@ Line 261: / Line 321: @@
 ===== Strain =====
-* '''Most commonly used strains in the US (2):'''
+* Most commonly used strains in the US (2):
-*# '''BCG Tice'''
+*# BCG Tice
-*# '''BCG Connaught'''
+*# BCG Connaught
 * '''Insufficient evidence to recommend a particular strain of BCG'''
@@ Line 269: / Line 329: @@
 * '''<span style="color:#ff0000">Induction</span>'''
 ** '''Two-hour intravesical instillation administered <span style="color:#ff0000">weekly over 6 weeks</span>'''
-** '''Treatments are typically begun 2-4 weeks after tumor resection, allowing time for re-epithelialization, which minimizes the potential for intravasation of live bacteria and systemic side effects'''
+** '''Treatments are typically begun 2-4 weeks after tumor resection''', allowing time for re-epithelialization, which minimizes the potential for intravasation of live bacteria and systemic side effects
 * '''<span style="color:#ff0000">Maintenance'''
 ** '''Two-hour intravesical instillation administered <span style="color:#ff0000">weekly over 3 weeks at 3, 6, 12, 18, 24, 30 and 36 months</span>, counting from the beginning of induction therapy.'''
@@ Line 275: / Line 335: @@
 ===== Instillation =====
 * '''A urinalysis is usually performed immediately before instillation to further confirm absence of infection or significant bleeding to decrease the likelihood of systemic uptake of BCG.'''
-* '''In the event of a traumatic catheterization, the treatment should be delayed for several days to 1 week'''
+* In the event of a traumatic catheterization, the treatment should be delayed for several days to 1 week
-* '''After instillation, some clinicians have advocated that the patient turn from side to side to bathe the entire urothelium, but there is no scientific support for this practice. Fluid, diuretic, and caffeine restriction before instillation limits dilution of the agent by urine and facilitates adequate retention of the agent for 2 hours.'''
+* After instillation, some clinicians have advocated that the patient turn from side to side to bathe the entire urothelium, but there is no scientific support for this practice. Fluid, diuretic, and caffeine restriction before instillation limits dilution of the agent by urine and facilitates adequate retention of the agent for 2 hours.
-* '''Patients are usually instructed to clean the toilet with bleach, although there is no demonstrable risk of close contact infection.'''
+* Patients are usually instructed to clean the toilet with bleach, although there is no demonstrable risk of close contact infection.
 ===== Adverse events[https://pubmed.ncbi.nlm.nih.gov/30526332/] =====
-* '''Most commonly occur in the first year of therapy'''
+* Most commonly occur in the first year of therapy
-* '''Serious toxicity occurs in ≈5% of patients'''
+* Serious toxicity occurs in ≈5% of patients
 * Pathogenesis
 **Hypothesized mechanisms leading to adverse events (2):[https://pubmed.ncbi.nlm.nih.gov/11886488/]
@@ Line 291: / Line 351: @@
 *'''<span style="color:#ff0000">Clinically classified as local vs. systemic</span>'''
 ** '''<span style="color:#ff0000">Local</span>'''
-*** '''Occurs in approximately 2/3 of patients'''
+*** Occurs in approximately 2/3 of patients
-*** '''Result of BCG-contaminated urine'''
+*** Result of BCG-contaminated urine
-*** '''Can occur anywhere along the genitourinary tract'''
+*** Can occur anywhere along the genitourinary tract
-*** '''<span style="color:#ff0000">Most common local adverse event: cystitis-like symptoms</span> (hematuria, urgency, dysuria and increased urinary frequency)'''
+*** '''<span style="color:#ff0000">Most common local adverse event: cystitis-like symptoms</span>''' (hematuria, urgency, dysuria and increased urinary frequency)
-**** '''Can occur in up to 71% of patients'''
+**** Can occur in up to 71% of patients
-**** '''Should be expected in the period immediately following BCG administration'''
+**** Should be expected in the period immediately following BCG administration
-**** '''Urinalysis and urine cultures do not yield evidence of infection'''
+**** Urinalysis and urine cultures do not yield evidence of infection
-***** '''Must be distinguished from bacterial cystitis, which should demonstrate evidence of infection at urinalysis and/or in urine cultures and requires treatment with antibiotics.'''
+***** Must be distinguished from bacterial cystitis, which should demonstrate evidence of infection at urinalysis and/or in urine cultures and requires treatment with antibiotics.
-**** '''Symptoms usually last 1–2 days; however, the degree and duration of symptoms tend to increase with subsequent BCG instillations'''
+**** Symptoms usually last 1–2 days; however, the degree and duration of symptoms tend to increase with subsequent BCG instillations
-*** '''Other local adverse events'''
+*** Other local adverse events
-**** '''Bladder contracture'''
+**** Bladder contracture
-**** '''Prostate: granulomatous prostatitis, prostate abscess'''
+**** Prostate: granulomatous prostatitis, prostate abscess
 ***** '''Granulomatous prostatitis'''
-****** '''Common following intravesical BCG therapy'''
+****** Common following intravesical BCG therapy
-****** '''May be due to reflux from the prostatic urethra to the prostatic ducts'''
+****** May be due to reflux from the prostatic urethra to the prostatic ducts
-****** '''Majority of patients with GP are asymptomatic'''
+****** Majority of patients with GP are asymptomatic
-****** '''Can result in abnormal digital rectal exam or abnormal PSA'''
+****** Can result in abnormal digital rectal exam or abnormal PSA
 ****** '''Appearance on MRI can mimic prostate cancer'''
 ****** '''Management'''
 ******* '''Asymptomatic: no intervention; if patient on maintenance BCG, can be continued.'''
-**** '''Scrotum: granulomatous epididymo-orchitis, testicular abscess'''
+**** Scrotum: granulomatous epididymo-orchitis, testicular abscess
-**** '''Upper urinary tract: pyelonephritis, renal abscess, renal granuloma, ureteral stricture'''
+**** Upper urinary tract: pyelonephritis, renal abscess, renal granuloma, ureteral stricture
-**** '''Penis: balanitis'''
+**** Penis: balanitis
 ** '''<span style="color:#ff0000">Systemic</span>'''
-*** '''Occurs in approximately 1/3 of patients'''
+*** Occurs in approximately 1/3 of patients
-*** '''Result of BCG dissemination to other sites via the bloodstream'''
+*** Result of BCG dissemination to other sites via the bloodstream
 *** '''<span style="color:#ff0000">Most common systemic adverse event: fever</span>'''
-**** '''Indicates adequate immune activation and is associated with a more favorable anti-tumor response'''
+**** Indicates adequate immune activation and is associated with a more favorable anti-tumor response
-**** '''Usually mild (<38.5ºC), lasting for less than 48 hours and accompanied by malaise and nausea.'''
+**** Usually mild (<38.5ºC), lasting for less than 48 hours and accompanied by malaise and nausea.
-**** '''Persistent (> 48h) and high fever (> 38.5ºC) should prompt a complete workup for infection'''
+**** Persistent (> 48h) and high fever (> 38.5ºC) should prompt a complete workup for infection
 *** '''<span style="color:#ff0000">Most serious systemic adverse event: sepsis</span>'''
 **** '''Occurs in 1:15,000 patients'''
@@ Line 338: / Line 398: @@
 ** '''See [https://www.cua.org/system/files/Guideline-Files/7367_NMIBC%2520Guideline_Epub.pdf Table 6] from 2021 CUA NMIBC Guidelines'''
 ** '''Isoniazid, rifampin, and cycloserine are used for systemic BCG toxicity'''
-** '''Maneuvers to improve tolerability include reducing BCG dose and/or decreasing dwell time'''
+** Maneuvers to improve tolerability include reducing BCG dose and/or decreasing dwell time
-*** '''The effect''' '''of BCG dose on toxicity is unclear'''
+*** The effect of BCG dose on toxicity is unclear
 ==== Interferon (IFN) ====
-* '''Multiple anti-tumor properties'''
+* Multiple anti-tumor properties
-* '''<span style="color:#ff0000">More expensive as a solitary agent and less effective than BCG or intravesical chemotherapy</span> in eradicating residual disease, preventing recurrence of papillary disease, and treating CIS; however, it can occasionally be effective in patients in whom BCG has failed'''
+* '''<span style="color:#ff0000">More expensive as a solitary agent and less effective than BCG or intravesical chemotherapy</span>''' in eradicating residual disease, preventing recurrence of papillary disease, and treating CIS; however, it can occasionally be effective in patients in whom BCG has failed
 == Combination intravesical therapy ==
@@ Line 355: / Line 415: @@
 *** '''Advantages:'''
 **** '''Some activity in BCG failures, but may not be more effective than BCG alone'''
-***** 2017 Cochrane Review
+***** [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6464648/ 2017 Cochrane Review]
 ***** '''Studies: 5 RCTs'''
 ***** '''Population: 1231 patients with NMIBC''' (Ta and T1 superficial bladder cancer, with or without carcinoma in situ, treated with TUR)
@@ Line 418: / Line 478: @@
 === Management options in BCG unresponsive disease ===
-* '''<span style="color:#ff0000">See</span> [[CUA/AUA: Non-muscle Invasive Bladder Cancer (2021 CUA/2016 AUA))|2016 AUA/2021 CUA NMBIC]] <span style="color:#ff0000">Guideline Notes</span>'''
+* '''<span style="color:#ff0000">See</span> [[CUA & AUA: Non-muscle Invasive Bladder Cancer (2021 CUA & 2024 AUA)|2024 AUA/2021 CUA NMBIC]] <span style="color:#ff0000">Guideline Notes</span>'''
 * '''<span style="color:#ff0000">Standard of care: radical cystectomy + lymph node dissection'''
 ** '''<span style="color:#ff0000">BCG-unresponsive with CIS or HG Ta: a second-line intravesical therapy might be considered before radical cystectomy'''
@@ Line 426: / Line 486: @@
 *# '''<span style="color:#ff0000">Intravesical nadofaragene firadenovec'''
 *# '''<span style="color:#ff0000">BCG plus N-803'''
+*# '''<span style="color:#ff0000">Valrubicin[https://pubmed.ncbi.nlm.nih.gov/38265030/]'''
 ** Chemoradiation should not be recommended for patients with BCG-unresponsive CIS
 * '''<span style="color:#ff0000">BCG-unresponsive who are unfit for or refuse to undergo radical cystectomy[https://pubmed.ncbi.nlm.nih.gov/33938798/]'''
@@ Line 431: / Line 492: @@
 *# '''<span style="color:#ff0000">Sequential intravesical gemcitabine/docetaxel[https://pubmed.ncbi.nlm.nih.gov/31821066/ §] (induction plus maintenance)'''
 *# '''<span style="color:#ff0000">Other combination intravesical therapy (e.g., sequential gemcitabine/MMC, BCG + interferon if available)'''
-*# '''<span style="color:#ff0000">Single-agent intravesical therapy (MMC, epirubicin, docetaxel, gemcitabine)'''
+*# '''<span style="color:#ff0000">Single-agent intravesical therapy (MMC, epirubicin, docetaxel, gemcitabine, valrubicin)'''
 *#* For BCG-unresponsive patients undergoing intravesical chemotherapy, sequential combination of drugs is favoured instead of single-agent regimens
 *#* See [https://www.cua.org/system/files/Guideline-Files/7367_NMIBC%2520Guideline_Epub.pdf Table 5] from 2021 CUA NMIBC Guidelines for dosing
@@ Line 438: / Line 499: @@
 *#** '''<span style="color:#ff0000">>2 BCG induction courses is not recommended due to high failure rate</span>''' <br>
-* '''<span style="color:#ff0000">Pembrolizumab'''
+==== <span style="color:#ff0000">Pembrolizumab ====
-** Systemic immunotherapy for NMIBC
+* Systemic immunotherapy for NMIBC
-** '''MOA: PD-1 checkpoint inhibitor'''
+* '''MOA: PD-1 checkpoint inhibitor'''
-** Dose: 200 mg IV q3weeks for up to 24 months
+* Dose: 200 mg IV q3weeks for up to 24 months
-** '''<span style="color:#ff00ff">KEYNOTE-057 (Lancet Oncology 2021)'''
+* '''<span style="color:#ff00ff">KEYNOTE-057 (Lancet Oncology 2021)'''
-*** Population: 96 patients with BCG-unresponsive CIS who were ineligible for or declined to undergo radical cystectomy
+** Population: 96 patients with BCG-unresponsive CIS who were ineligible for or declined to undergo radical cystectomy
-****BCG-unresponsive disease was defined as
+***BCG-unresponsive disease was defined as
-*****Stage progression at 3 months (or up to 4 weeks either side) despite adequate BCG induction therapy alone OR
+****Stage progression at 3 months (or up to 4 weeks either side) despite adequate BCG induction therapy alone OR
-*****Persistent high-risk non-muscle-invasive bladder cancer at 6 months (or up to 4 weeks either side) after adequate BCG therapy OR
+****Persistent high-risk non-muscle-invasive bladder cancer at 6 months (or up to 4 weeks either side) after adequate BCG therapy OR
-*****Recurrent high-risk non-muscle-invasive bladder cancer within 9 months after the last BCG instillation despite adequate BCG therapy.
+****Recurrent high-risk non-muscle-invasive bladder cancer within 9 months after the last BCG instillation despite adequate BCG therapy.
-*** '''Single arm study''': 200 mg of pembrolizumab IV q3 weeks for 24 months or until recurrence, progression or limiting toxicity
+** '''Single arm study''': 200 mg of pembrolizumab IV q3 weeks for 24 months or until recurrence, progression or limiting toxicity
-*** Primary outcome: clinical complete response rate (absence of high-risk non-muscle-invasive bladder cancer or progressive disease), assessed by cystoscopy and urine cytology approximately 3 months after the first dose of study drug.
+** Primary outcome: clinical complete response rate (absence of high-risk non-muscle-invasive bladder cancer or progressive disease), assessed by cystoscopy and urine cytology approximately 3 months after the first dose of study drug.
-*** Results
+** Results
-**** Median follow-up: 36.4 months
+*** Median follow-up: 36.4 months
-**** Complete response in 39 patients (41%) at 3 months
+*** Complete response in 39 patients (41%) at 3 months
-**** Median duration of response was 16.2 months
+*** Median duration of response was 16.2 months
-****Median duration of treatment was 4.2 months
+***Median duration of treatment was 4.2 months
-*****91% discontinued treatment; primary reasons for discontinuation were persistent disease and recurrent disease or stage progression to T1 disease
+****91% discontinued treatment; primary reasons for discontinuation were persistent disease and recurrent disease or stage progression to T1 disease
-****49% of initial responders and non-responders who discontinued pembrolizumab subsequently underwent radical cystectomy
+***49% of initial responders and non-responders who discontinued pembrolizumab subsequently underwent radical cystectomy
-**** Adverse events
+*** Adverse events
-*****Treatment-related adverse events in 66% of patients
+****Treatment-related adverse events in 66% of patients
-******13% of patients had grade 3 or 4 treatment-related adverse events
+*****13% of patients had grade 3 or 4 treatment-related adverse events
-******22% of patients had immune-related adverse events of any grade
+*****22% of patients had immune-related adverse events of any grade
-*****Most common treatment-related adverse events: hyponatremia (3%), arthralgia (2%)
+****Most common treatment-related adverse events: hyponatremia (3%), arthralgia (2%)
-*****Most common serious treatment-related adverse events: pneumonitis (3%), colitis (2%)
+****Most common serious treatment-related adverse events: pneumonitis (3%), colitis (2%)
-*****Treatment-related adverse events led to pembrolizumab interruption in 13% of patients
+****Treatment-related adverse events led to pembrolizumab interruption in 13% of patients
-*** [https://pubmed.ncbi.nlm.nih.gov/34051177/ Balar, Arjun V., et al.] "Pembrolizumab monotherapy for the treatment of high-risk non-muscle-invasive bladder cancer unresponsive to BCG (KEYNOTE-057): an open-label, single-arm, multicentre, phase 2 study." ''The Lancet Oncology'' (2021).
+** [https://pubmed.ncbi.nlm.nih.gov/34051177/ Balar, Arjun V., et al.] "Pembrolizumab monotherapy for the treatment of high-risk non-muscle-invasive bladder cancer unresponsive to BCG (KEYNOTE-057): an open-label, single-arm, multicentre, phase 2 study." ''The Lancet Oncology'' (2021).
-* '''<span style="color:#ff0000">Nadofaragene firadenovec (Adstiladrin)</span>'''
+*In January 2020, received FDA approval for the treatment of patients with BCG-unresponsive, high-risk, NMIBC with CIS with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy
-** '''MOA: a non-replicating adenovirus vector (rAd-INFa/Syn3) together with recombinant IFN-alpha2b. When given intravesically, the virus is transduced into bladder cells and the IFN-alpha2b gene is incorporated by the DNA. IFNalpha2b protein, which has antitumour activity, is then produced.'''
-*** '''<span style="color:#ff00ff">Single-arm trial</span>'''
+==== <span style="color:#ff0000">Nadofaragene firadenovec (Adstiladrin)</span> ====
-*** '''Population: 157 patients with BCG-unresponsive non-muscle-invasive bladder cancer'''
-*** '''Results:'''
+===== Mechanism of action =====
-**** '''53% of patients with (with or without a high-grade Ta or T1 tumour) had a complete response within 3 months of the first dose and this response was maintained in 46% of 55 patients at 12 months.'''
+* A non-replicating adenovirus vector (rAd-INFa/Syn3) together with recombinant IFN-alpha2b. When given intravesically, the virus is transduced into bladder cells and the IFN-alpha2b gene is incorporated by the DNA. IFNalpha2b protein, which has antitumour activity, is then produced.
-*** '''Boorjian, Stephen A., et al. "Intravesical nadofaragene firadenovec gene therapy for BCG-unresponsive non-muscle-invasive bladder cancer: a single-arm, open-label, repeat-dose clinical trial." ''The Lancet Oncology'' 22.1 (2021): 107-117.'''
-* '''Oportuzumab monatox (Vicineum)'''
+==== Efficacy ====
-** '''MOA: specific antibody to Epithelial Cell Adhesion Molecule (EpCAM) fused to a Pseudomonas toxin that binds specifically to bladder cancer cells.'''
+* '''<span style="color:#ff00ff">Single-arm trial</span>'''
-* '''BCG plus N-803'''
+** Population: 157 patients with BCG-unresponsive non-muscle-invasive bladder cancer
-** '''MOA: N-803 is an IL-15 superagonist antibody cytokine fusion protein that can be co-administered intravesically with BCG to induce activation and proliferation of endogenous natural killer (NK) cells and CD8+ T-cells without inducing a T-reg response.'''
+** Results:
+*** 53% of patients with (with or without a high-grade Ta or T1 tumour) had a complete response within 3 months of the first dose and this response was maintained in 46% of 55 patients at 12 months.
+** [https://pubmed.ncbi.nlm.nih.gov/33253641/ Boorjian, Stephen A., et al.] "Intravesical nadofaragene firadenovec gene therapy for BCG-unresponsive non-muscle-invasive bladder cancer: a single-arm, open-label, repeat-dose clinical trial." ''The Lancet Oncology'' 22.1 (2021): 107-117.
+*In December 2022, received FDA approval for patients with high-risk BCG-unresponsive NMIBC with CIS with or without papillary tumors.
+===== Technique =====
+* Instilled every 3 months as a suspension
+==== Oportuzumab monatox (Vicineum) ====
+* MOA: specific antibody to Epithelial Cell Adhesion Molecule (EpCAM) fused to a Pseudomonas toxin that binds specifically to bladder cancer cells.
+==== BCG plus N-803 ====
+* MOA: N-803 is an IL-15 superagonist antibody cytokine fusion protein that can be co-administered intravesically with BCG to induce activation and proliferation of endogenous natural killer (NK) cells and CD8+ T-cells without inducing a T-reg response.
 == Role of “timely” cystectomy ==
+* '''See section on [[CUA & AUA: Non-muscle Invasive Bladder Cancer (2021 CUA & 2024 AUA)#Indications for Cystectomy in NMIBC|Indications for Cystectomy in NMIBC from AUA/CUA Guidelines]]'''
 * Despite local therapy, many cases of high-grade NMIBC will progress to invasion and risk of cancer death
 * '''The term “early” cystectomy is based on fact that they are performed before the traditional surgical indication of documented muscle invasion. A reasonable goal might be “timely” cystectomy for patients at risk.'''
 ** Cystectomy for CIS or persistent high-grade papillary disease after 2 courses of intravesical therapy, is the standard of care and should not be considered “early.”
 * '''<span style="color:#ff0000">Indications:</span>'''
-** '''See 2016 AUA/2021 CUA NMBIC Guideline Notes'''
+** <span style="color:#ff0000">'''See'''</span> '''[[CUA/AUA: Non-muscle Invasive Bladder Cancer (2021 CUA/2016 AUA))|2016 AUA/2021 CUA NMBIC]] <span style="color:#ff0000">Guideline Notes</span>'''
 ** Campbell’s:
 *** High grade and invading deeply into lamina propria
@@ Line 496: / Line 571: @@
 == Surveillance and Prevention ==
-* '''See 2016 AUA/2021 CUA NMBIC Guideline Notes on recommendations for surveillance, which are based on risk-classification'''
+* <span style="color:#ff0000">'''See'''</span> '''[[CUA/AUA: Non-muscle Invasive Bladder Cancer (2021 CUA/2016 AUA))|2016 AUA/2021 CUA NMBIC]] <span style="color:#ff0000">Guideline Notes</span> on recommendations for surveillance, which are based on risk-classification'''
 * At 10 years, ≈30% of patients remain free of tumor progression or recurrence, so close follow-up is mandatory
 * Most protocols include cystoscopy and urinary cytology every 3 months for 18-24 months after the initial diagnosis, then every 6 months for the following 2 years, and then annually, resetting the clock with each newly identified tumor
@@ Line 504: / Line 579: @@
 * '''Extravesical surveillance'''
 ** '''<span style="color:#ff0000">Incidence of UTUC after bladder cancer: 3% (range 1.6% (low-risk) to 4.1% (high-risk))</span>'''
-** '''See 2016 AUA/2021 CUA NMBIC Guideline Notes on recommendations for upper-tract surveillance'''
+** <span style="color:#ff0000">'''See'''</span> '''[[CUA/AUA: Non-muscle Invasive Bladder Cancer (2021 CUA/2016 AUA))|2016 AUA/2021 CUA NMBIC]] <span style="color:#ff0000">Guideline Notes</span> on recommendations for upper-tract surveillance'''
 ** Modality: CT and intravenous urography
 * '''Prostatic urethral UC'''
@@ Line 518: / Line 593: @@
 == Questions ==
-See 2016 AUA/2021 CUA NMIBC Guideline Notes Questions
+<span style="color:#ff0000">'''See'''</span> '''[[CUA/AUA: Non-muscle Invasive Bladder Cancer (2021 CUA/2016 AUA))|2016 AUA/2021 CUA NMBIC]] <span style="color:#ff0000">Guideline Notes</span>'''
-== Next Chapter: Muscle invasive bladder cancer ==
+== Next Chapter: [[Muscle-Invasive Bladder Cancer]] ==
 == Additional References ==