Editing Non-Muscle Invasive Bladder Cancer (section)

== Intravesical therapy ==

* '''Either chemotherapy or immunotherapy'''
* '''Either therapeutic''' (treatment of CIS or residual non-visible tumour), '''prophylactic''' (prevention of recurrence and progression of disease'''), or adjuvant in the immediate postoperative setting'''

=== 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'''

=== Intravesical immunotherapy ===
* '''<span style="color:#ff0000">Mechanism of action</span>'''
** '''<span style="color:#ff0000">Results in a massive local immune response which activates cell-mediated cytotoxic mechanisms</span>'''
*** '''Response to intravesical immunotherapy may be limited if a patient has an immunosuppressive disease or by advanced age'''

==== Bacille Calmette-Guérin (BCG)[https://pubmed.ncbi.nlm.nih.gov/30526332/] ====

===== History =====
* Originally developed as a vaccine for tuberculosis
* 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'''
*Mycobacterium bovis is closely related to mycobacterium tuberculosis

===== Efficacy =====
*'''<span style="color:#ff0000">Superior to chemotherapy to reduce recurrence (ARR 25% vs. 12%), and only agent to reduce progression (ARR 4%)</span>'''

====== Recurrence ======
* '''<span style="color:#ff00ff">Cochrane review</span>'''
** 6 randomized trials involving 585 patients
** The total number of patients presenting with tumour recurrence at 12 months was 79 (26%) in the BCG plus TUR group and 144 (51%) in the TUR alone group (absolute risk reduction in recurrence of 25%)
** Intravesical Bacillus Calmette-Guerin in Ta and T1 Bladder Cancer. [https://pubmed.ncbi.nlm.nih.gov/11034738/ Cochrane Database Syst Rev. 2000;(4):CD001986.]
* '''BCG has been shown to be superior to doxorubicin or epirubicin and similar to mitomycin with regard to preventing recurrence.'''

====== Progression ======
* '''<span style="color:#ff00ff">SWOG-8216/38</span>'''
** 262 patients
** Randomized to 1 year maintenance doxorubicin vs. 1-years BCG
** Results:
*** Progression rate 15% BCG vs. 37% doxorubicin
** A randomized trial of intravesical doxorubicin and immunotherapy with bacille Calmette-Guérin for transitional-cell carcinoma of the bladder. [https://pubmed.ncbi.nlm.nih.gov/1922207/ N Engl J Med. 1991 Oct 24;325(17):1205-9.]
* '''<span style="color:#ff00ff">Meta-analysis of trials evaluating BCG on risk of NMIBC progression</span>'''
** 24 trials with progression information on 4,863 patients
** Results:
*** Based on a median follow-up of 2.5 years and a maximum of 15 years, progression rate 10% BCG vs. 14% control (OR 0.73, p = 0.001'''), absolute risk reduction in progression of 4%.''' The percent of patients with progression was low reflecting the short follow-up and relatively low risk patients entered in many of the trials. The size of the treatment effect was similar in patients with papillary tumors and in those with carcinoma in situ. '''However, only patients receiving maintenance BCG benefited from reduced risk of progression.'''
*** There was no statistically significant difference in treatment effect for either overall survival or death due to bladder cancer.
** Intravesical bacillus Calmette-Guerin reduces the risk of progression in patients with superficial bladder cancer: a meta-analysis of the published results of randomized clinical trials. [https://pubmed.ncbi.nlm.nih.gov/12394686/ J Urol. 2002 Nov;168(5):1964-70.]
* '''Increased risk of side effects compared to intravesical chemotherapy; BCG should be used cautiously for patients with low-risk disease because of concern about side effects'''
** BCG has a greater risk of adverse events, both local (granulomatous cystitis, dysuria, hematuria) and systemic (fever), as compared to most intravesical chemotherapies. Thus, when the recurrence risk is moderate and intravesical therapy is felt appropriate, a better-tolerated intravesical chemotherapy may have a better risk to benefit ratio than BCG when the primary goal is to prevent recurrence.
** '''<span style="color:#ff00ff">Cochrane Review on BCG vs. MMC in NMIBC</span>'''
*** 6 trials involving 1527 patients
*** Results
**** Tumour recurrence was significantly reduced with intravesical BCG compared to MMC only in the subgroup of patients at high risk of tumour recurrence. However, there was no difference in terms of disease progression or survival, and the decision to use either agent might be based on adverse events and cost.
*** Intravesical bacillus Calmette-Guerin versus mitomycin C for Ta and T1 bladder cancer. [https://pubmed.ncbi.nlm.nih.gov/12917955/ Cochrane Database Syst Rev. 2003;(3):CD003231.]

===== Indications =====
* '''<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'''
** '''Treatment of residual tumour'''
*** '''Intravesical BCG can effectively treat residual papillary lesions but should not be used as a substitute for surgical resection'''
** '''<span style="color:#ff0000">Maintenance BCG</span>'''
*** '''The optimal dose and the treatment schedule for BCG are undetermined, but results are better with maintenance therapy, if tolerated'''
*** '''<span style="color:#ff00ff">SWOG 8507'''
**** '''Population: 550 patients'''
**** '''Randomized to <span style="color:#ff0000">induction (weekly x 6 weeks)</span> vs. induction + maintenance'''
***** '''<span style="color:#ff0000">Maintenance therapy consisted of intravesical</span> and percutaneous <span style="color:#ff0000">BCG each week for 3 weeks given 3, 6, 12, 18, 24, 30 and 36 months from initiation of induction therapy.</span>'''
**** '''Results'''
***** '''5-year recurrence-free survival 41% in induction only and 60% in induction + maintenance; <span style="color:#ff0000">absolute risk reduction in recurrence of 19%</span>'''
***** '''Only 16% of patients tolerated the full dose-schedule regimen. Two thirds of the patients who stopped BCG because of side effects did so in the first 6 months, suggesting that the side effects do not increase appreciably with additional time on therapy.'''
**** '''Maintenance bacillus Calmette-Guerin immunotherapy for recurrent TA, T1 and carcinoma in situ transitional cell carcinoma of the bladder: a randomized Southwest Oncology Group Study. [https://pubmed.ncbi.nlm.nih.gov/10737480/ J Urol. 2000 Apr;163(4):1124-9.]'''
*** '''BCG''' '''dose reduction''' 
**** '''In general, a decrease in toxicity with no statistical difference in efficacy has been noted in small series'''
**** '''CUA: Several European studies have demonstrated that the BCG dose can be reduced to one-third or one-quarter with a reduction in toxicity but comparable efficacy.'''
***** '''However, Morales and colleagues have shown that dose reduction is associated with decreased efficacy in North American patients. Recently, a randomized trial of 1355 patients with intermediate and high-risk NMIBC compared full-dose and one-third dose BCG and 1-year and 3-year maintenance. This trial showed that a 3-year maintenance of full-dose BCG had superior recurrence-free rates without increased toxicity. No differences in progression or overall survival were demonstrated.'''
**** '''AUA: In favor of standard dose BCG, a meta-analysis demonstrated improved recurrence free survival with standard dose as compared to a reduced dose but no difference in progression free survival.'''
***** '''The largest individual study of 1,355 patients (EORTC 30962) compared different BCG strengths (full dose versus 1/3 dose) and different BCG maintenance schedules (1 year versus 3 years) and found no difference in recurrence free survival between 1/3 dose and full dose administered for either 1 year or 3 years. However, in high-risk patients (patients with high grade, T1 tumors), the 3 year full dose schedule had an improved recurrence free survival as compared to the 1 year 1/3 dose schedule, leading the authors to recommend full dose BCG in this patient subgroup'''

===== Contraindications =====
* '''<span style="color:#ff0000">Absolute contraindications </span><span style="color:#0000ff">SHIT-IT</span> <span style="color:#ff0000">(6):</span>'''
*# '''<span style="color:#0000ff">S</span><span style="color:#ff0000">epsis, personal history of BCG sepsis</span>'''
*#* '''Use of BCG in patients with ileal conduit urinary diversion is associated with up to a 10% risk of sepsis due to absorption'''
*# '''<span style="color:#0000ff">H</span><span style="color:#ff0000">ematuria, gross</span>; intravasation risk'''
*# '''<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><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;</span> intravasation risk'''
* '''<span style="color:#ff0000">Relative contraindications (4):</span>'''
*# '''<span style="color:#ff0000">UTI (intravasation risk)</span>'''
*# '''<span style="color:#ff0000">Liver disease (precludes treatment with isoniazid if sepsis occurs)</span>'''
*# '''<span style="color:#ff0000">Poor overall performance status</span>'''
*# '''<span style="color:#ff0000">Advanced age</span>'''
* '''No or insufficient data on potential contraindications'''
** Patients with prosthetic materials
** Ureteral reflux
** Anti–tumor necrosis factor medications (theoretically predispose to BCG sepsis)
* '''Not contraindications'''
** '''Previous BCG vaccine'''
*** 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
*** Population: 3915 patients from Taiwan with newely diagnosed bladder cancer and received adjuvant intravesical BCG therapy within 3 months after the surgery
*** Results:
**** 187 (4.8%) had been previously diagnosed with tuberculosis infection
**** 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.
*** Campbell's 11th edition: relative contraindication, risk theorized but unknown

===== Dose =====
* '''<span style="color:#ff0000">Full dose: 120 mg (full dose) BCG in 50cc NS to dwell in bladder for 2 hours</span>'''
* '''<span style="color:#ff0000">Quinolones in particular may affect the viability of BCG and should be avoided if possible during the course of BCG treatments</span>'''

===== Strain =====
* Most commonly used strains in the US (2):
*# BCG Tice
*# BCG Connaught
* '''Insufficient evidence to recommend a particular strain of BCG'''

===== Schedule =====
* '''<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
* '''<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.'''

===== 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
* 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.

===== Adverse events[https://pubmed.ncbi.nlm.nih.gov/30526332/] =====
* Most commonly occur in the first year of therapy
* Serious toxicity occurs in ≈5% of patients
* Pathogenesis
**Hypothesized mechanisms leading to adverse events (2):[https://pubmed.ncbi.nlm.nih.gov/11886488/]
**#Bacterial mediated: local, and possibly blood-borne, dissemination of the attenuated BCG strain
**#*Respond readily to antituberculous therapy, despite solid evidence of AFB infection
**#Non-bacterial mediated: sterile hypersensitivity reaction
**#*May be more delayed in appearance
**#*Responds readily to corticosteroids
*'''<span style="color:#ff0000">Clinically classified as local vs. systemic</span>'''
** '''<span style="color:#ff0000">Local</span>'''
*** Occurs in approximately 2/3 of patients
*** Result of BCG-contaminated urine
*** 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)
**** Can occur in up to 71% of patients
**** Should be expected in the period immediately following BCG administration
**** 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.
**** Symptoms usually last 1–2 days; however, the degree and duration of symptoms tend to increase with subsequent BCG instillations
*** Other local adverse events
**** Bladder contracture
**** Prostate: granulomatous prostatitis, prostate abscess
***** '''Granulomatous prostatitis'''
****** Common following intravesical BCG therapy
****** May be due to reflux from the prostatic urethra to the prostatic ducts
****** Majority of patients with GP are asymptomatic
****** 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
**** Upper urinary tract: pyelonephritis, renal abscess, renal granuloma, ureteral stricture
**** Penis: balanitis
** '''<span style="color:#ff0000">Systemic</span>'''
*** Occurs in approximately 1/3 of patients
*** 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
**** 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
*** '''<span style="color:#ff0000">Most serious systemic adverse event: sepsis</span>'''
**** '''Occurs in 1:15,000 patients'''
**** '''Potentially fatal'''
*** Other systemic adverse events
**** Malaise
**** Musculoskeletal: spondylodiscitis, intramuscular abscess, infected hardware, skin rash, arthralgia
**** Vascular: mycotic pseudoaneurysm
**** Pulmonary: pneumonitis
**** Hepatic: granulomatous hepatitis
**** Lymphatic: granulomatous lymphadenitis
**** Peritoneal: peritonitis
**** Opthalmic: choroiditis
**** Salivary: parotitis
****Endocrine: hypercalcemia from systemic granulomatosis[https://pubmed.ncbi.nlm.nih.gov/11886488/]
* '''Management'''
** '''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
*** The effect of BCG dose on toxicity is unclear

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