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Non-Muscle Invasive Bladder Cancer: Difference between revisions

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==== Immediate instillation following TURBT ====
==== Immediate instillation following TURBT ====
</span>
 
* '''<span style="color:#ff0000">Indications</span>'''
===== '''<span style="color:#ff0000">Rationale</span>''' =====
** <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">Reduces risk of tumour recurrence (absolute risk reduction ≈12%);</span> <span style="color:#ff0000">no benefit of chemotherapy on progression</span>'''
**'''<span style="color:#ff0000">Particularly effective for the initial presentation of a (3):</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">Solitary</span>'''
** '''<span style="color:#ff00ff">Meta-analysis evaluating intravesical chemotherapy on risk of recurrence</span>'''
**# '''<span style="color:#ff0000">Low-grade</span>'''
*** 13 studies including 2548 patients
**# '''<span style="color:#ff0000">Papillary tumor</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).
*** '''<span style="color:#ff0000">The incremental benefit in patients with recurrent or multiple tumors is limited.</span>'''
*** 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.
*** '''<span style="color:#ff0000">No benefit has been found in patients with high-grade disease.</span>'''
*** 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.
*** '''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'''
 
*'''Contraindications'''
===== '''Mechanism of action''' =====
*# '''After extensive resection'''
* '''The two primary theories for recurrent tumor formation:'''
*# '''Bladder perforation is suspected'''
** '''Genetic field defect exists with multiple new tumors spontaneously arising within the bladder'''
*# '''Significant bleeding'''
** '''Local reimplantation of tumor cells after tumor resection'''
*#*'''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)'''
*** '''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">Rationale</span>'''
*** '''Immediate instillation of intravesical chemotherapy may reducing tumor cell implantation'''
**'''<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>'''
* '''Intravesical chemotherapy may also have an ablative effect on small occult tumours'''
*** '''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:#ff00ff">Meta-analysis evaluating intravesical chemotherapy on risk of recurrence</span>'''
===== '''<span style="color:#ff0000">Indications</span>''' =====
**** 13 studies including 2548 patients
* <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">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).
'''Contraindications'''
**** 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.
# '''After extensive resection'''
**** 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.
# '''Bladder perforation is suspected'''
** '''Mechanism of action'''
# '''Significant bleeding'''
*** '''The two primary theories for recurrent tumor formation:'''
#*'''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)'''
**** '''Genetic field defect exists with multiple new tumors spontaneously arising within the bladder'''
 
**** '''Local reimplantation of tumor cells after tumor resection'''
===== '''<span style="color:#ff0000">Efficacy</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”'''
*'''Number needed to treat to prevent 1 recurrence: 8'''
***** '''Immediate instillation of intravesical chemotherapy may reducing tumor cell implantation'''
**'''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'''
*** '''Intravesical chemotherapy may also have an ablative effect on small occult tumours'''
*'''<span style="color:#ff0000">Particularly effective for the initial presentation of a (3):</span>'''
*'''<span style="color:#ff0000">Commonly used intravesical agents for single post-operative intravesical instillation of chemotherapy (5):</span>'''
*# '''<span style="color:#ff0000">Solitary</span>'''
*# '''<span style="color:#ff0000">Gemcitabine</span>''' (SWOG S0337[https://pubmed.ncbi.nlm.nih.gov/29801011/ §])
*# '''<span style="color:#ff0000">Low-grade</span>'''
*##Mechanism of action: inhibits DNA synthesis
*# '''<span style="color:#ff0000">Papillary tumor</span>'''
*##Dose: 2g in 100mL[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5315602/]
** '''<span style="color:#ff0000">The incremental benefit in patients with recurrent or multiple tumors is limited.</span>'''
*# '''<span style="color:#ff0000">Mitomycin C (MMC)</span>'''
** '''<span style="color:#ff0000">No benefit has been found in patients with high-grade disease.</span>'''
*##Mechanism of action: alkylating agent that inhibits DNA replication
 
*##Dose: 40g in 20-40mL
===== <span style="color:#ff0000">Commonly Used Agents (5):</span> =====
*# '''<span style="color:#ff0000">Doxorubicin</span>'''
# '''<span style="color:#ff0000">Gemcitabine</span>''' (SWOG S0337[https://pubmed.ncbi.nlm.nih.gov/29801011/ §])
*# '''<span style="color:#ff0000">Epirubicin</span>'''
##Mechanism of action: inhibits DNA synthesis
*# '''<span style="color:#ff0000">Pirarubicin</span>'''
##Dose: 2g in 100mL[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5315602/]
** '''All equal efficacy as per CUA Guidelines'''
# '''<span style="color:#ff0000">Mitomycin C (MMC)</span>'''
*** 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).
##Mechanism of action: alkylating agent that inhibits DNA replication
** '''Thiotepa has also been evaluated'''
##Dose: 40g in 20-40mL
*'''<span style="color:#ff0000">Steps for Successful Perioperative Administration of Intravesical Chemotherapy</span>'''
# '''<span style="color:#ff0000">Doxorubicin</span>'''
*# '''Include intent to administer perioperative chemotherapy (and agent) on actual operative schedule.'''
# '''<span style="color:#ff0000">Epirubicin</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 has 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.'''
===== <span style="color:#ff0000">Steps for Successful Perioperative Administration of Intravesical Chemotherapy</span> =====
*# '''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>[https://pubmed.ncbi.nlm.nih.gov/16925493/ §]'''
# '''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">Local irritative symptoms (most common complication)</span>/chemical cystitis'''
****'''<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">Rash/Contact dermatitis (second most common complication)</span>'''
***'''Given side effects of MMC, consider preferential use of gemcitabine which is better tolerated'''
** '''<span style="color:#ff0000">UTI</span>'''
** '''<span style="color:#ff0000">Thiotepa</span>'''
** '''<span style="color:#ff0000">Hematuria</span>'''
*** '''<span style="color:#ff0000">Local irritative symptoms</span>'''
** '''<span style="color:#ff0000">Fever/chills</span>'''
*** '''<span style="color:#ff0000">Myelosuppresion</span>'''
** '''<span style="color:#ff0000">Cutaneous hand/foot desquamation</span>'''
**** '''The low molecular weight of thiotepa predisposes to systemic absorption and myelosuppression'''
** '''<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 ====
==== Induction and maintenance chemotherapy ====
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