Non-Muscle Invasive Bladder Cancer

See 2016 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

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 & Evaluation

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):
    1. Genetic field defect exists with multiple new tumors spontaneously arising within the bladder
    2. 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):$$
  1. Prior recurrence rate (<1 year)
  2. Number of tumours
  3. Tumour size (>3 cm)

Progression

• Progression rates (defined by higher grade or stage): ≈20-30%
• Risk factors (3):$$
  1. Grade (most important)
     • Grade more important than stage (unlike other cancers where stage is more important)
       • High-grade tumors progress with similar frequency regardless of whether they are invasive (T1) or non-invasive (Ta)
       • Stage Ta are usually LG; however, ≈7% of Ta disease is HG
  2. Stage (second most important)
     • TaLG: high recurrence rate (≈55%), but much lower stage progression rate ≈6%
     • T1HG: high recurrence rate (≈45%) and high progression rate ≈17% [different numbers than Chapter 93]
  3. CIS
     • If CIS is treated only with TURBT,
       • High risk of recurrence (as high as 90%)
       • High risk (> 50%) for progressing to muscle-invasive disease.
     • Even patients with a complete response to intravesical BCG will experience progression in 30% to 40% of cases on longitudinal follow-up
     • Concomitant CIS is associated with significantly increased risk of disease progression and disease-specific mortality

Other risk factors

• Mentioned in 2021 CUA NMIBC Guidelines (5):
  1. Age > 70 yr
  2. Extensive invasion of the lamina propria
     • Extent of invasion of T1 tumours has been evaluated using two different criteria:
     1. Micrometric: evaluates the millimetric extent of invasion into the lamina propria
     2. Microanatomic: evaluates the level of invasion in relation to the muscularis mucosa (T1a – no muscularis mucosa invasion, T1b – invasion at the level of the muscularis mucosa and T1c – invasion beyond the muscularis mucosa)
     • No single approach has been universally adopted
  3. Lymphovascular invasion (LVI)
     • Retrospective studies demonstrate that the presence of LVI is an independent factor for progression in patients with high-risk NMIBC.
       • Use of LVI as a prognostic variable on transurethral resection (TUR) specimen requires prospective validation
     • In NIMBC, LVI is associated with increased risk of recurrence and progression in BCG-treated patients with T1 NMIBC§
  4. Aggressive histological variants such as (3): micropapillary, plasmacytoid, and sarcomatoid
     • See Bladder Cancer: Pathology & TNM Staging
     • Associated with under-staging and early progression to muscle invasive disease
  5. First assessment after TURBT
     • Persistent disease at the first surveillance cystoscopy after induction intravesical treatment has been shown to be a risk factor associated with progression
• Mentioned in Campbell’s
  • Tumour architecture: papillary vs. sessile
  • Status of the remaining urothelium

Cancer-specific Survival

• 70-85% in high-grade NMIBC[1], higher in low-grade disease

Estimating Prognosis

• European Organization for Research and Treatment of Cancer (EORTC) Risk Tables
  • Provides individualized probability of recurrence and progression of NMIBC
  • Developed from individual patient data from 2596 patients diagnosed with Ta/T1 tumours who were randomized in 7 EORTC trials.
  • Estimates based on can be calculated based on (6):
    1. Number of tumors
    2. Tumor size
    3. Prior recurrence rate
    4. T category
    5. Concomitant carcinoma in situ
    6. 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

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):
  1. Reduce tumor cell implantation
  2. Have an ablative effect on small occult tumours/residual microscopic tumor at the site of TURBT

Indications

2024 AUA

• Consider in (2):
  1. Low-risk (suspected or known) NMIBC
  2. Intermediate-risk (suspected or known) NMIBC

CUA (3):

• Recommended in

1. Low-risk NMIBC
2. Intermediate-risk NMIBC
3. Patients with ≤ 1 recurrence/year and EORTC recurrence score < 5

Contraindications

1. After extensive resection
2. Bladder perforation is suspected
3. Significant bleeding
   • 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

• No benefit of immediate chemotherapy on progression or survival[2]
  • Only BCG has been shown to delay or reduce high-grade tumor progression.
    • No chemotherapy trials have achieved a significant reduction in progression
• Reduces risk of tumour recurrence
  • Number needed to treat to prevent 1 recurrence: 8 (absolute risk reduction ≈12%)
    • 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. 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
      • 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):
    1. Solitary
    2. Low-grade
    3. 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):

1. Gemcitabine (SWOG 0337§)
   1. Mechanism of action: inhibits DNA synthesis
   2. Dose: 2g in 100mL[3]
2. Mitomycin C (MMC)
   1. Mechanism of action: alkylating agent that inhibits DNA replication
   2. Dose: 40g in 20-40mL
3. Epirubicin
4. Doxorubicin
5. 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 and combination epirubicin and mitomycin C[4] have also been evaluated

Steps for Successful Perioperative Administration of Intravesical Chemotherapy

1. Include intent to administer perioperative chemotherapy (and agent) on actual operative schedule.
2. Contact pharmacy before surgery to have medication available. A written prescription may be required.
3. 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.
4. Administer chemotherapeutic agent through catheter outflow port in recovery room within 6 hours of operation, and clamp outflow tubing with hemostat to allow retention.
   • Efficacy of post-operative instillation significantly decreases if given beyond 24h
5. Give order for outflow tubing to be opened 1 hour after administration and for irrigation, to be opened to gravity drainage for next 30-60 minutes.
6. Remove Foley catheter and discard in biohazard container.
7. Wear gloves

Methods to optimize MMC administration (may reduce recurrence rate further) (4):

1. Higher concentration (40mg in 20mL of sterile tumour)
2. Urinary alkalinisation by using sodium bicarbonate to reduce drug degradation
3. Pre-treatment dehydration
4. Complete bladder drainage prior to intravesical therapy

Adverse events§

• MMC
  • Local irritative symptoms (most common complication)/chemical cystitis
  • Rash/Contact dermatitis (second most common complication)
  • UTI
  • Hematuria
  • Fever/chills
  • Cutaneous hand/foot desquamation
  • Decreased bladder capacity as a result of contractures
  • Calcified eschars
  • Added difficulty of subsequent cystectomy
  • Serious sequelae and rare deaths have occurred, especially in patients with perforation during resection.
    • Chemotherapy should be withheld in patients with extensive resection or when there is concern about perforation.
  • Given side effects of MMC, consider preferential use of gemcitabine which is better tolerated
• Thiotepa
  • Local irritative symptoms
  • Myelosuppresion
    • 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

• Mechanism of action
  • Results in a massive local immune response which activates cell-mediated cytotoxic mechanisms
    • Response to intravesical immunotherapy may be limited if a patient has an immunosuppressive disease or by advanced age

Bacille Calmette-Guérin (BCG)[5]

History

• Originally developed as a vaccine for tuberculosis
• In 1976, 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

• Superior to chemotherapy to reduce recurrence (ARR 25% vs. 12%), and only agent to reduce progression (ARR 4%)

Recurrence

• Cochrane review
  • 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. 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

• SWOG-8216/38
  • 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. N Engl J Med. 1991 Oct 24;325(17):1205-9.
• Meta-analysis of trials evaluating BCG on risk of NMIBC progression
  • 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. 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.
  • Cochrane Review on BCG vs. MMC in NMIBC
    • 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. Cochrane Database Syst Rev. 2003;(3):CD003231.

Indications

• See 2016 AUA/2021 CUA NMBIC Guideline Notes
• 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
  • Maintenance BCG
    • The optimal dose and the treatment schedule for BCG are undetermined, but results are better with maintenance therapy, if tolerated
    • SWOG 8507
      • Population: 550 patients
      • Randomized to induction (weekly x 6 weeks) vs. induction + maintenance
        • Maintenance therapy consisted of intravesical and percutaneous BCG each week for 3 weeks given 3, 6, 12, 18, 24, 30 and 36 months from initiation of induction therapy.
      • Results
        • 5-year recurrence-free survival 41% in induction only and 60% in induction + maintenance; absolute risk reduction in recurrence of 19%
        • 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. 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

• Absolute contraindications SHIT-IT (6):
  1. Sepsis, personal history of BCG sepsis
     • Use of BCG in patients with ileal conduit urinary diversion is associated with up to a 10% risk of sepsis due to absorption
  2. Hematuria, gross; intravasation risk
  3. Immunosuppressed and immunocompromised patients
     • Small series suggest this may not be an absolute contraindication
  4. TURBT, immediately after resection due to risk of intravasation and septic death
  5. Incontinence (total)
  6. Traumatic catheterization; intravasation risk
• Relative contraindications (4):
  1. UTI (intravasation risk)
  2. Liver disease (precludes treatment with isoniazid if sepsis occurs)
  3. Poor overall performance status
  4. Advanced age
• 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[6]
  • 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
    • 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

• Full dose: 120 mg (full dose) BCG in 50cc NS to dwell in bladder for 2 hours
• Quinolones in particular may affect the viability of BCG and should be avoided if possible during the course of BCG treatments

Strain

• Most commonly used strains in the US (2):
  1. BCG Tice
  2. BCG Connaught
• Insufficient evidence to recommend a particular strain of BCG

Schedule

• Induction
  • Two-hour intravesical instillation administered weekly over 6 weeks
  • 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
• Maintenance
  • Two-hour intravesical instillation administered weekly over 3 weeks at 3, 6, 12, 18, 24, 30 and 36 months, 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[7]

• Most commonly occur in the first year of therapy
• Serious toxicity occurs in ≈5% of patients
• Pathogenesis
  • Hypothesized mechanisms leading to adverse events (2):[8]
    1. Bacterial mediated: local, and possibly blood-borne, dissemination of the attenuated BCG strain
       • Respond readily to antituberculous therapy, despite solid evidence of AFB infection
    2. Non-bacterial mediated: sterile hypersensitivity reaction
       • May be more delayed in appearance
       • Responds readily to corticosteroids
• Clinically classified as local vs. systemic
  • Local
    • Occurs in approximately 2/3 of patients
    • Result of BCG-contaminated urine
    • Can occur anywhere along the genitourinary tract
    • Most common local adverse event: cystitis-like symptoms (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
  • Systemic
    • Occurs in approximately 1/3 of patients
    • Result of BCG dissemination to other sites via the bloodstream
    • Most common systemic adverse event: fever
      • 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
    • Most serious systemic adverse event: sepsis
      • 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[9]
• Management
  • See 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
• More expensive as a solitary agent and less effective than BCG or intravesical chemotherapy 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

Combination intravesical therapy

• Combination intravesical chemotherapy
  • No major benefit compared to BCG monotherapy
• BCG combined with intravesical chemotherapy
  • No major benefit compared to BCG monotherapy
• BCG combined with other immunotherapy
  • BCG and interferon-α
    • Advantages:
      • Some activity in BCG failures, but may not be more effective than BCG alone
        • 2017 Cochrane Review
        • Studies: 5 RCTs
        • Population: 1231 patients with NMIBC (Ta and T1 superficial bladder cancer, with or without carcinoma in situ, treated with TUR)
          • Note that these are not BCG failure patients
        • Comparison: BCG plus IFN‐α vs. BCG alone
        • Results:
          • No difference in risk of recurrence
          • No difference in risk of progression
          • No difference in cancer-specific survival
      • Favourable side-effect profile
        • Usually better than BCG alone because most of the side effects are related to the BCG and its dose is reduced in this regimen.
    • Disadvantages
      • More expensive than BCG monotherapy
  • Ongoing clinical trials are examining different drug combinations as well as surgical techniques, such as chemo-hyperthermia

Other treatments

• Device-assisted therapy
  • Electromotive drug administration (EMDA) with intravesical MMC
    • Capable of increasing the uptake of drugs by cancer cells through electric current
    • Has shown promising results; however, further studies are needed to validate their efficacy
  • Chemohyperthermia (CHT) with intravesical MMC
    • Radiofrequency elevates the temperature of the urothelium to 41–44ºC while intravesical chemotherapy is delivered.
    • Has shown promising results; however, further studies are needed to validate their efficacy
• Photodynamic therapy (PDT)
  • Performed by administering a photosensitizing agent such as porfimer sodium (Photofrin) systemically or HAL intravesically. 2-3 days after the substance has cleared from the normal tissue (for Photofrin), the patient is given an intravesical treatment with red laser light (630 nm) for 12-20 minutes. Intravesical intralipid allows for more uniform distribution of laser light. After excitation by light, the photosensitizer reacts with molecular oxygen to form free radicals and reactive singlet oxygen, which are cytotoxic.
  • The response rate in CIS patients from combined series is 66%
• Radiation therapy
  • Typically restricted to individuals who refuse cystectomy after the failure of intravesical therapy or who are unsuitable for major surgery

BCG failure

• See Figure

Categories of BCG failure (4)

• 2016 International Bladder Cancer Group Definitions[10]

1. BCG-intolerant
   • Disease persistence as a result of inability to receive adequate BCG* because of toxicity.
     • Adequate BCG is defined as at least 5-6 weekly instillations of an induction course followed by at least one maintenance cycle (consisting of at least 2 out of 3 weekly BCG treatments) or a second induction cycle (whereby at least 2 of 6 weekly instillations were received).
2. BCG-relapsing
   • Recurrence of high-grade disease after achieving a disease-free state at 6 months after adequate BCG.
     • Sub-stratified into early (<12 months) vs. intermediate (12-24 months) vs. late (>24 months)
       • Prognosis improved with increasing duration of disease-free interval
3. BCG-refractory
   • Persistent high-grade disease at 6 months despite adequate BCG treatment
   • Any stage or grade progression by 3 months after the first BCG cycle (eg. initial Ta/TaHG or CIS then 3 months BCG then T1HG)
     • BCG-refractory patients are at increased risk of progression and worse 5-year survival rates when compared to patients with a complete response to induction therapy
4. BCG-unresponsive
   • Includes
     • All BCG refractory tumours
     • BCG-relapse within 6 months of last BCG exposure
     • CIS within 12 months of completion of adequate BCG exposure
   • BCG-unresponsive disease implies patients being previously treated with adequate BCG (see above)
   • Meant to denote a subgroup of patients at highest risk of recurrence and progression for whom additional BCG therapy is not a feasible option.

• BCG resistant (described in 2015 CUA NMIBC Guidelines)
  • Recurrence or persistence of disease at 3 months after induction cycle but of lesser stage or grade which subsequently is no longer present at 6 months
• Prognosis: BCG intolerance > BCG relapsing > BCG refractory (worst prognosis)
• Low-grade recurrences during or after BCG are not considered BCG failure

Management options in BCG unresponsive disease

• See 2016 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
• BCG-unresponsive with CIS who are unfit for or refuse to undergo radical cystectomy (4):
  1. Intravenous pembrolizumab
  2. Intravesical oportuzumab monatox
  3. Intravesical nadofaragene firadenovec
  4. BCG plus N-803
  • Chemoradiation should not be recommended for patients with BCG-unresponsive CIS
• BCG-unresponsive who are unfit for or refuse to undergo radical cystectomy[11]
  1. Clinical trial
  2. Sequential intravesical gemcitabine/docetaxel§ (induction plus maintenance)
  3. Other combination intravesical therapy (e.g., sequential gemcitabine/MMC, BCG + interferon if available)
  4. Single-agent intravesical therapy (MMC, epirubicin, docetaxel, gemcitabine)
     • For BCG-unresponsive patients undergoing intravesical chemotherapy, sequential combination of drugs is favoured instead of single-agent regimens
     • See Table 5 from 2021 CUA NMIBC Guidelines for dosing
  5. Repeat induction BCG
     • In patients with NMIBC treated with an induction course of BCG (without maintenance) who later develop recurrence of disease (BCG relapse), a second induction course may achieve 30-50% response rates.
       • >2 BCG induction courses is not recommended due to high failure rate
         

• Pembrolizumab
  • Systemic immunotherapy for NMIBC
  • MOA: PD-1 checkpoint inhibitor
  • Dose: 200 mg IV q3weeks for up to 24 months
  • KEYNOTE-057 (Lancet Oncology 2021)
    • Population: 96 patients with BCG-unresponsive CIS who were ineligible for or declined to undergo radical cystectomy
      • 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
        • 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.
    • 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.
    • Results
      • Median follow-up: 36.4 months
      • Complete response in 39 patients (41%) at 3 months
      • Median duration of response was 16.2 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
      • 49% of initial responders and non-responders who discontinued pembrolizumab subsequently underwent radical cystectomy
      • Adverse events
        • Treatment-related adverse events in 66% of patients
          • 13% of patients had grade 3 or 4 treatment-related adverse events
          • 22% of patients had immune-related adverse events of any grade
        • Most common treatment-related adverse events: hyponatremia (3%), arthralgia (2%)
        • Most common serious treatment-related adverse events: pneumonitis (3%), colitis (2%)
        • Treatment-related adverse events led to pembrolizumab interruption in 13% of patients
    • 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)
  • 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
    • Population: 157 patients with BCG-unresponsive non-muscle-invasive bladder cancer
    • 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.
    • 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)
  • 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 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.
  • Cystectomy for CIS or persistent high-grade papillary disease after 2 courses of intravesical therapy, is the standard of care and should not be considered “early.”
• Indications:
  • See 2016 AUA/2021 CUA NMBIC Guideline Notes
  • Campbell’s:
    • High grade and invading deeply into lamina propria
    • Exhibit lymphovascular invasion
    • Associated with diffuse CIS
    • In diverticula
    • Substantially involve the distal ureters or prostatic urethra
    • Refractory to initial therapy
    • Too large or anatomically inaccessible to be removed in their entirety endoscopically
    • Patients who understand the risks and benefits of bladder preservation versus cystectomy and request definitive therapy

Surveillance and Prevention

• See 2016 AUA/2021 CUA NMBIC Guideline Notes on recommendations for surveillance, which are based on risk-classification
• At 10 years, ≈30% of patients remain free of tumor progression or recurrence, so close follow-up is mandatory
• Most protocols include cystoscopy and urinary cytology every 3 months for 18-24 months after the initial diagnosis, then every 6 months for the following 2 years, and then annually, resetting the clock with each newly identified tumor
  • Most studies and a meta-analysis have failed to identify benefit of intraurethral injection of local anesthetics at the time of cystoscopy, and two recent studies actually found that pain experience was higher with the use of local anesthetics than in patients cystoscoped using aqueous lubricant alone. Considering the fact that anesthetic agents can partially cloud visualization, this ubiquitous practice should be reconsidered.
  • Use of a video monitor allows the patient to see and understand the findings, theoretically distracting them from any discomfort. Men who are able to do so tolerate the procedure with ≈50% less pain than those who cannot see their findings on the monitor. This has not been found to be of significant benefit in women, probably because of the straighter urethra
  • Although not indicated for routine screening and evaluation of asymptomatic microscopic hematuria, urinary cytology may be used in the surveillance of bladder cancer for certain patients as it possesses a high sensitivity and positive predictive value for high-grade tumors and CIS
• Extravesical surveillance
  • Incidence of UTUC after bladder cancer: 3% (range 1.6% (low-risk) to 4.1% (high-risk))
  • See 2016 AUA/2021 CUA NMBIC Guideline Notes on recommendations for upper-tract surveillance
  • Modality: CT and intravenous urography
• Prostatic urethral UC
  • Secondary tumor involvement of the prostatic urethra and ducts by UC may be detected in 10-15% of patients with high-risk non–muscle-invasive disease within 5 years and in 20-40% within 10 years.
  • Management
    • See Urothelial Carcinoma of the Prostate Chapter Notes
    • Involvement of the prostatic ducts by low-grade urothelial should usually be managed by complete TURP for disease eradication and to facilitate contact of intravesical therapy to the prostatic urethra.
    • Involvement of the ducts by high-grade disease is best managed by radical cystoprostatectomy +/u urethrectomy

Secondary prevention strategies

• Smoking cessation, increased fluid intake, and a low-fat diet may all reduce the risk of recurrence

Questions

See 2016 AUA/2021 CUA NMBIC Guideline Notes

Additional References

• Wein AJ, Kavoussi LR, Partin AW, Peters CA (eds): CAMPBELL-WALSH UROLOGY, ed 11. Philadelphia, Elsevier, 2015, chap 93
• Bhindi, Bimal, et al. "Canadian Urological Association guideline on the management of non-muscle invasive bladder cancer." Canadian Urological Association Journal 15.8 (2021).
• Green, Daniel B., et al."Complications of intravesical BCG immunotherapy for bladder cancer." Radiographics 39.1 (2019): 80-94.