Editing Non-Muscle Invasive Bladder Cancer (section)

=== Intravesical chemotherapy ===

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

===== Mechanism of action =====
* '''Immediate instillation of intravesical chemotherapy may (2):'''
*# '''Reduce tumor cell implantation'''
*# '''Have an ablative effect on small occult tumours/residual microscopic tumor at the site of TURBT'''

===== Indications =====

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

* '''<span style="color:#ff0000">Consider in</span>''' '''<span style="color:#ff0000">(2):</span>'''
*# '''<span style="color:#ff0000">Low-risk (suspected or known) NMIBC</span>''' 
*# '''<span style="color:#ff0000">Intermediate-risk (suspected or known) NMIBC</span>'''

====== 2021 CUA ======
* '''<span style="color:#ff0000">Recommended (2):</span>'''
*# '''<span style="color:#ff0000">Intermediate-risk NMIBC</span>'''
*# '''<span style="color:#ff0000">Patients with ≤1 recurrence/year and European Organisation for Research and Treatment of Cancer (EORTC) recurrence score <5</span>'''
* '''<span style="color:#ff0000">Should be offered (1):</span>'''
** '''<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)'''

===== 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>'''

===== Commonly Used Agents (5): =====
# '''<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/]
# '''<span style="color:#ff0000">Mitomycin C (MMC)</span>'''
##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">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 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 =====
# '''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.'''
# '''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.'''
# '''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">Efficacy of post-operative instillation significantly decreases if given beyond 24h</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.'''
# '''Remove Foley catheter and discard in biohazard container.'''
# '''Wear gloves'''

===== <span style="color:#ff0000">Methods to optimize MMC administration</span> (may reduce recurrence rate further) <span style="color:#ff0000">(4): =====
# '''<span style="color:#ff0000">Higher concentration (40mg in 20mL of sterile tumour)</span>'''
# '''<span style="color:#ff0000">Urinary alkalinisation</span> by using sodium bicarbonate to reduce drug degradation'''
# '''<span style="color:#ff0000">Pre-treatment dehydration</span>'''
# '''<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">MMC</span>'''
** '''<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">UTI</span>'''
** '''<span style="color:#ff0000">Hematuria</span>'''
** '''<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 ====
*'''Benefit of induction + maintanence chemotherapy vs. induction therapy alone is unclear, unlike BCG where the efficacy of maintenance has been established'''
**'''Intravesical chemotherapy has less toxicity than intravesical BCG, leading many in the European community to favor this approach.'''
***'''If patient develops recurrence during induction/maintenance chemotherapy, consider treating with induction + maintenance BCG'''
**** '''BCG has demonstrated superiority to repeat courses of chemotherapy in this setting'''