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~~/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'''

'''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 ==

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

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

** Majority of Ta tumours are 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

== Diagnosis and Evaluation ==

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

* '''≈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'''

*** Majority of Ta tumours are 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

== ~~Prognosis~~ of NMIBC ==

== Genetics ==

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

* '''Microsatellite analysis amplifies DNA repeats in the genome'''

* '''Primary tumour genetic abnormalities in'''

** '''Low-malignant potential NMIBC: chromosome 9, FGFR-3'''

** '''High-malignant potential NMIBC: deletion of RB and TP53'''

* '''Alterations of tumour proten 53 (p53), RB, and PTEN are associated with CIS''' and also carry a very poor prognosis

** '''p53'''

*** '''Most common mutation found in invasive (T2 or higher) bladder tumors'''

*** 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)

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** '''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 ===

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**# 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

~~== Genetics of NMIBC ==~~

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

* '''Microsatellite analysis amplifies DNA repeats in the genome'''

* '''Primary tumour genetic abnormalities in'''

** '''Low-malignant potential NMIBC: chromosome 9, FGFR-3'''

** '''High-malignant potential NMIBC: deletion of RB and TP53'''

* '''Alterations of tumour proten 53 (p53), RB, and PTEN are associated with CIS''' and also carry a very poor prognosis

** '''p53'''

*** '''Most common mutation found in invasive (T2 or higher) bladder tumors'''

*** 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

== Intravesical therapy ==

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

===== ~~Rationale~~ =====

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

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

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

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

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

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

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

*** 13 studies including 2548 patients

*** '''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).

===== Indications =====

*** 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.

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

~~=====~~ '''~~Mechanism of action''' ==~~===

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

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

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

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

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

** '''~~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”'''

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

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

===== '''~~Indications~~''' ~~=====~~

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

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

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

'''~~Contraindications~~'''

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

# '''After extensive resection'''

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

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

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

# '''Significant bleeding'''

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

===== Contraindications =====

# '''After extensive resection'''

# '''Suspected bladder perforation'''

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

#*'''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)'''

===== '''~~Efficacy~~''' =~~====~~

===== Efficacy =====

*'''Number needed to treat to prevent 1 recurrence: 8'''

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

**'''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'''

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

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

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

*# '''Solitary'''

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

*# '''Low-grade'''

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

*# '''Papillary tumor'''

***'''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.'''

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

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

# '''Gemcitabine''' (SWOG ~~S0337~~[https://pubmed.ncbi.nlm.nih.gov/29801011/ §])

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

##Mechanism of action: inhibits DNA synthesis

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

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

##Dose: 40g in 20-40mL

# '''Epirubicin'''

# '''Doxorubicin'''

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

# '''Pirarubicin'''

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

** 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'''

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

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

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

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

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

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

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

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

* '''MMC'''

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

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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.

*** [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.

* ~~'''~~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.'''

@@ Line 1: / Line 1: @@
 [[Category:Bladder Cancer]]
-<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">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 ==
+* '''<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">Of patients with NMIBC, 70% are Ta, 20% are T1, and 10% are CIS</span>'''
+** Majority of Ta tumours are 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
+== Diagnosis and Evaluation ==
 * '''See [[Bladder Cancer: Diagnosis and Evaluation|Bladder Cancer: Diagnosis & Evaluation]]'''
-* '''<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>'''
-*** Majority of Ta tumours are 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
-== Prognosis of NMIBC ==
+== Genetics ==
+* '''Tumor suppressor genes are mainly activated by''' allelic deletion of one allele followed by '''point mutations''' of the remaining allele
+* '''Microsatellite analysis amplifies DNA repeats in the genome'''
+* '''<span style="color:#ff0000">Primary tumour genetic abnormalities in</span>'''
+** '''<span style="color:#ff0000">Low-malignant potential NMIBC: chromosome 9, FGFR-3</span>'''
+** '''<span style="color:#ff0000">High-malignant potential NMIBC: deletion of RB and TP53</span>'''
+* '''Alterations of tumour proten 53 (p53), RB, and PTEN are associated with CIS''' and also carry a very poor prognosis
+** '''p53'''
+*** '''Most common mutation found in invasive (T2 or higher) bladder tumors'''
+*** 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)
@@ Line 59: / Line 79: @@
 ** '''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 ===
@@ Line 72: / Line 96: @@
 **# 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
-== Genetics of NMIBC ==
-* '''Tumor suppressor genes are mainly activated by''' allelic deletion of one allele followed by '''point mutations''' of the remaining allele
-* '''Microsatellite analysis amplifies DNA repeats in the genome'''
-* '''<span style="color:#ff0000">Primary tumour genetic abnormalities in</span>'''
-** '''<span style="color:#ff0000">Low-malignant potential NMIBC: chromosome 9, FGFR-3</span>'''
-** '''<span style="color:#ff0000">High-malignant potential NMIBC: deletion of RB and TP53</span>'''
-* '''Alterations of tumour proten 53 (p53), RB, and PTEN are associated with CIS''' and also carry a very poor prognosis
-** '''p53'''
-*** '''Most common mutation found in invasive (T2 or higher) bladder tumors'''
-*** 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
 == Intravesical therapy ==
@@ Line 95: / Line 106: @@
 ==== Immediate instillation following TURBT ====
-===== <span style="color:#ff0000">Rationale</span> =====
+===== Mechanism of action =====
-*'''<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>'''
+* '''Immediate instillation of intravesical chemotherapy may (2):'''
-** '''BCG is the only agent shown to delay or reduce high-grade tumor progression.''' No chemotherapy trials have achieved a significant reduction in progression
+*# '''Reduce tumor cell implantation'''
-** '''<span style="color:#ff00ff">Meta-analysis evaluating intravesical chemotherapy on risk of recurrence</span>'''
+*# '''Have an ablative effect on small occult tumours/residual microscopic tumor at the site of TURBT'''
-*** 13 studies including 2548 patients
-*** '''<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).
+===== Indications =====
-*** 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.
+====== 2024 AUA ======
-===== '''Mechanism of action''' =====
+* '''<span style="color:#ff0000">Consider in</span>''' '''<span style="color:#ff0000">(2):</span>'''
-* '''The two primary theories for recurrent tumor formation:'''
+*# '''<span style="color:#ff0000">Low-risk (suspected or known) NMIBC</span>'''
-** '''Genetic field defect exists with multiple new tumors spontaneously arising within the bladder'''
+*# '''<span style="color:#ff0000">Intermediate-risk (suspected or known) NMIBC</span>'''
-** '''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”'''
-*** '''Immediate instillation of intravesical chemotherapy may reducing tumor cell implantation'''
-* '''Intravesical chemotherapy may also have an ablative effect on small occult tumours'''
-===== '''<span style="color:#ff0000">Indications</span>''' =====
+====== 2021 CUA ======
-* <span style="color:#ff0000">'''See'''</span> '''[[CUA & AUA: Non-muscle Invasive Bladder Cancer (2021 CUA & 2020 AUA)|2020 AUA/2021 CUA NMBIC]] <span style="color:#ff0000">Guideline Notes</span>'''
+* '''<span style="color:#ff0000">Recommended (2):</span>'''
-'''Contraindications'''
+*# '''<span style="color:#ff0000">Intermediate-risk NMIBC</span>'''
-# '''After extensive resection'''
+*# '''<span style="color:#ff0000">Patients with ≤1 recurrence/year and European Organisation for Research and Treatment of Cancer (EORTC) recurrence score <5</span>'''
-# '''Bladder perforation is suspected'''
+* '''<span style="color:#ff0000">Should be offered (1):</span>'''
-# '''Significant bleeding'''
+** '''<span style="color:#ff0000">All patients with presumed low-risk NMIBC at TURBT</span>'''
+===== Contraindications =====
+# '''<span style="color:#ff0000">After extensive resection'''
+# '''<span style="color:#ff0000">Suspected bladder perforation'''
+# '''<span style="color:#ff0000">Significant bleeding requiring bladder irrigation'''
 #*'''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">Efficacy</span>''' =====
+===== Efficacy =====
-*'''Number needed to treat to prevent 1 recurrence: 8'''
+*'''<span style="color:#ff0000">No benefit of immediate chemotherapy on progression or survival[https://pubmed.ncbi.nlm.nih.gov/38265030/]</span>'''
-**'''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'''
+**'''Only BCG has been shown to delay or reduce high-grade tumor progression.'''
-*'''<span style="color:#ff0000">Particularly effective for the initial presentation of a (3):</span>'''
+***No chemotherapy trials have achieved a significant reduction in progression
-*# '''<span style="color:#ff0000">Solitary</span>'''
+*'''<span style="color:#ff0000">Reduces risk of tumour recurrence</span>'''
-*# '''<span style="color:#ff0000">Low-grade</span>'''
+**'''<span style="color:#ff0000">Number needed to treat to prevent 1 recurrence: 8 (absolute risk reduction ≈12%)'''
-*# '''<span style="color:#ff0000">Papillary tumor</span>'''
+***'''<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>'''
-===== <span style="color:#ff0000">Commonly Used Agents (5):</span> =====
+===== Commonly Used Agents (5): =====
-# '''<span style="color:#ff0000">Gemcitabine</span>''' (SWOG S0337[https://pubmed.ncbi.nlm.nih.gov/29801011/ §])
+# '''<span style="color:#ff0000">Gemcitabine</span>''' (SWOG 0337[https://pubmed.ncbi.nlm.nih.gov/29801011/ §])
 ##Mechanism of action: inhibits DNA synthesis
 ##Dose: 2g in 100mL[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5315602/]
@@ Line 137: / Line 168: @@
 ##Mechanism of action: alkylating agent that inhibits DNA replication
 ##Dose: 40g in 20-40mL
+# '''<span style="color:#ff0000">Epirubicin</span>'''
 # '''<span style="color:#ff0000">Doxorubicin</span>'''
-# '''<span style="color:#ff0000">Epirubicin</span>'''
 # '''<span style="color:#ff0000">Pirarubicin</span>'''
 * '''All equal efficacy as per CUA Guidelines'''
 ** 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'''
+* '''Thiotepa and combination epirubicin and mitomycin C[https://pubmed.ncbi.nlm.nih.gov/36200115/] have also been evaluated'''
-===== <span style="color:#ff0000">Steps for Successful Perioperative Administration of Intravesical Chemotherapy</span> =====
+===== Steps for Successful Perioperative Administration of Intravesical Chemotherapy =====
 # '''Include intent to administer perioperative chemotherapy (and agent) on actual operative schedule.'''
 # '''Contact pharmacy before surgery to have medication available. A written prescription may be required.'''
@@ Line 160: / Line 191: @@
 # '''<span style="color:#ff0000">Complete bladder drainage prior to intravesical therapy</span>'''
-===== '''<span style="color:#ff0000">Adverse events</span>[https://pubmed.ncbi.nlm.nih.gov/16925493/ §]''' =====
+===== <span style="color:#ff0000">Adverse events</span>'''[https://pubmed.ncbi.nlm.nih.gov/16925493/ §]''' =====
 * '''<span style="color:#ff0000">MMC</span>'''
 ** '''<span style="color:#ff0000">Local irritative symptoms (most common complication)</span>/chemical cystitis'''
@@ Line 447: / 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 455: / 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 460: / 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 467: / 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.
-*** [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.
-* '''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.'''