Editing Non-Muscle Invasive Bladder Cancer (section)

==== 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