Bladder cancer - NMIBC

Bladder cancer - main discussion

Non-muscle invasive bladder cancer (NMIBC)

Stage Risk

Tis - carcinoma in situ (CIS). High-grade by definition

Typically flat erythematous lesion. Bluelight helps identification. Should biopsy prostatic urethra as well.

Risk of recurrence (untreated): 80%

Risk of progression to T2 (untreated): 40-80%

Risk of recurrence/progression after complete response to BCG: 20-30%
Ta - noninvasive papillary adenocarcinoma

LG
Risk of recurrence: up to 70% at 1 year

Risk of progression to T2: 5%

HG
Risk of progression to T1: 15-40%
Risk of progression to T2: 6-25%

T1 - invades subepithelial connective tissue

Significant risk of under-staging on TURBT.

Risk of recurrence: 70-80%

Risk of progression to T2: 50% in 3 years
  • Second-look TURBT indicated for HG Ta and T1, or incomplete first TURBT, or large (> 3 cm) or highly multifocal disease
    • HG Ta - half had residual disease; 15% were upstaged
    • T1 - half had residual disease; 30% were upstaged to T2
  • Immediate post-operative intravesical chemotherapy to reduce recurrence
    • Indications: consider in suspected or known low risk disease
      • Most helpful in single LG Ta tumor; less benefit for recurrent/multiple tumors or HG tumor
    • Give within 24 hrs of TURBT
    • Do not instill if extensive TURBT/risk of perforation as it delays healing
    • Mitomycin or gemcitabine; can reduce recurrence from 50% to 37% at 4 years (35% relative risk, 13% absolute risk)
      •  Destroys residual tumor and dispersed floating tumor cells to prevent reimplantation
      • Gemcitabine cheaper and less toxic

Other histologies

Urothelial papilloma

1-4% of urothelial neoplasms

Frondular with slender fibrovascular stalks

Benign, unclear what follow-up/surveillance should be?
Inverted urothelial papilloma

< 1% of urothelial neoplasms
Men in 50s-60s, a/w hematuria, occasionally obstructive symptoms

Typically solitary smooth lesion, up to several cm in size

Benign, no progression to cancer on 5-year f/u case-series, but occasionally a/w UC

Reasonable compromise: cysto at 1 year, then stop surveillance?
PUNLMP (Papillary urothelial neoplasm of low malignant potential)  

Frequently recur (30-40%) and progress to UC (30%)

Surveil as low-risk UC

Nephrogenic adenoma

Proliferation of exfoliated/implanted renal tubular cells

 A/w chronic urothelial inflammation

Benign
Cystitis glandularis A/w chronic urothelial inflammation Benign

Surveillance

  • Cysto 
  • Urine cytology - high specificity, low sensitivity. Obtain with intermediate and high risk disease
    • If positive cytology but negative cystoscopy - should consider random bladder biopsies + prostatic urethra biopsy, blue light cysto, upper tract imaging, upper tract washings/ureteroscopy
  • Upper tract imaging - only 0.8% have subsequent upper tract tumors; surveillance of limited value unless hematuria or high-grade tumor
Risk Tumor Cysto schedule Upper tract imaging
Low

Solitary LG Ta < 3 cm
PUNLMP

 3 mo after resection
If no recurrence - annual beginning 12 mo after resection
Consider cessation at 5yrs
consider cytology, tumor markers		 Not necessary unless + hematuria
Intermediate Multiple LG Ta or LG Ta > 3 cm
Recurrence within 1 year
HG Ta ≤ 3 cm
LG T1		 q3mo x 1-2 yrs
q6mo-1yr after 2 yrs
Consider cytology, tumor markers
Restart clock with each recurrence		 Consider esp for recurrence
Imaging for hematuria
High Recurrent HG Ta
HG Ta > 3 cm
HG T1
Any CIS, BCG failure, variant histology, LVI, HG prostatic urethral involvement		 q3mo x 2 yrs
q6mo x 2-3 yrs, then
Annually for lifetime
Cytology with each cysto
Consider tumor markers		 Imaging annually for 2 yr, then consider lengthening interval

Intravesical therapy

  • Chemo reduces recurrence but does not alter progression
  • BCG (immunotherapy) reduces recurrence AND progression (~30% risk reduction with maintenance BCG compared to chemo).
  • No advantage to combination chemo + BCG
  • Indications
    • Low risk - no inductive therapy (mod grade C)
    • Intermediate risk - 6 wk therapy (chemo or BCG) (Mod grade B)
      • Intravesical chemo probably equivalent to BCG - use chemo in BCG shortage, save BCG for high risk patients
    • High risk - 6 wk BCG (Strong grade B)
  • Logistics
    • Induction: 1 instillation per week x 6 weeks; patient has to hold in for 2 hrs.
    • Maintenance: weekly x 3 weeks at months: 3, 6, 12, 18, 24, 30, and 36
    • Rule out UTI, urothelial integrity disruption to avoid systemic absorption (e.g. UA to check for blood; do not give if +microhematuria)
  • Side effects: generally more common with BCG. Dysuria (60% with BCG), cytokine response (flu-like symptoms for 48-72 hrs), BCG sepsis (rare)

Intravesical BCG

  • Good Nature Review on BCG
    • Complete response in about 69% at 6 mo (84% if +maintenance)
    • Recurrence: risk reduction of 25-30% (higher with maintenance)
    • Progression: risk reduction of ~50%
    • Eventually fails in up to 50% of patients
      • 1-year RFS: 50-70%. 
  • Start BCG 3-4 weeks after TURBT (never within 2 weeks - risk of sepsis and death)
    • Do not use if significant immunosuppression
  • Wait 6 weeks after finishing BCG induction before repeat cystoscopy (needs time to work) - e.g. first cysto ~ 3 mo after start of therapy.
    • May need up to 6 mo to work in CIS
  • If eradicated after 1-2 courses, recommend maintenance BCG (triplet LAMM/SWOG protocol)
    • weekly x 3 weeks at months: 3, 6, 12, 18, 24, 30, and 36
    • x 1 year for intermediate-risk (Mod grade C)
    • x 3 years for high-risk (Mod grade B)
    • ***limit maintenance in era of BCG shortage...
  • BCG complications (EAU guidelines - Section 7.4.3.3)
    • Fever < 38.5C - hold BCG until symptoms resolve (generally within 48 hrs, probably immune response to BCG)
    • Fever > 101.5F (38.5C) for > 12-24 hours despite Tylenol - isoniazid 300 mg PO qd x 3 months (with vitamin B6 (pyridoxine)). 
      • CXR + urine cx for AFB but will take weeks/low yield; start treatment in meantime
      • EAU - recommend permanent discontinuation of BCG.
    • If septic or acute severe illness - isoniazid 300 mg, rifampin 600 mg, ethambutol 1200 mg daily x 6 mo. Early high-dose corticosteroids while symptomatic.
      • Do not give BCG ever again!

BCG failure defined as...

  Definition What to do
Intolerance can't tolerate side effects  
Resistant persistent disease after initial 6 wk induction Repeat BCG induction (Mod grade C)
~30% will achieve durable response with 2nd course
Refractory persistent disease after 2nd course of induction, evaluated at 6 months

Consider cystectomy for BCG unresponsive disease (Mod grade C)

  • for high-grade T1, consider RC for failure x 1 (Mod grade C)

No more BCG! (only 10-20% response with repeated courses)
Relapsed initial response, with early (< 1 yr) or late (> 1 yr) recurrence Can repeat BCG induction?
BCG unresponsive (after "adequate BCG") Encompasses refractory + early relapse (≤ 6 mo for Ta/T1, < 12 mo for CIS ± Ta/T1, or T1 present at 3 months)

Cystectomy is standard of care

  • Discussion of other therapies (gemcitabine, Valstar, Pembro etc) below
  • "Adequate BCG" = 5/6 induction doses, 2/3 maintenance doses
  • In times of BCG shortage, if resistant disease after 1st BCG course...
    • Multifocal/recurrent LG Ta
      • Switch to intravesical chemo, or use more office fulguration, do less frequent cysto
    • CIS or HG Ta
      • Try 2nd 3-6 wk induction course (20-30% will respond), don't call it "failure" until 6 mo cysto in case did not give enough time for BCG to work
    • HG T1
      • Risk of progression high with repeated courses, consider cystectomy at first sign of failure

BCG-unresponsive disease

  • Many clinical trials in progress (FDA guidance). General threshold - good therapy should exceed 50% CR at 6 mo; 30% 1-year disease-free survival; 25% at 18 mo.
Therapy Logistics Response rates
*Gemcitabine docetaxel doublet therapy (Steinberg J Urol 2020) gemcitabine 1g in 50 mL water (pH adjusted) x 1 hour, drain bladder, docetaxel 37.5 mg in 50 mL saline x 1-2 hours

CR - 60% at first surveillance

1-year RFS - 60%

2-year RFS - 34%

Cystectomy rate - 16%
*Pembro
FDA approved 2020 for BCG-unresponsive CIS (KEYNOTE 057)

systemic, q3wks x 2 years or until disease progression or AEs (median 10 cycles)

Side effects high - 13% Gr 3-4 adverse events

~$140,000 per year

CR - 41% at 3 months, median duration 16.2 mo.

- of CR, 46% maintained response > 12 mo, 33%  > 18 mo, 23% > 24 mo

1-year RFS (CIS) ~ 20%

1-year RFS (HG Ta/T1) - 44%
*Adstilidrin (nadofaragene firadenovec) - FDA approved 2022 (NCT 02773849)
Gene therapy - recombinant adenovirus delivers IFN alpha/2beta cDNA to bladder epithelium causing immune system activation

1 instillation q3mo x 5, then until recurrence or AE

~$50,000/dose

Gr 3-4 AE - 3.8%

CR - 53.4% at 3 mo (CIS +/- Ta/T1), 68% at 12 mo

1-year RFS 44%

5-year RFS 13% (CIS), 33% (Ta/T1)

Cystectomy rate - 50%
*Anktiva (N-803) + BCG
FDA approved Apr 2024 (QUILT 3.032)
IL-15-based immunostimulatory fusion protein (Nogapendekin alfa inbakicept-pmln)

Given with BCG
$35,000/dose ($450,000 first year)

Gr 3-4 AE - 3.6%

CR - 55% at 3 mo, 71% at any time

61% with CR have duration > 12 mo
Median duration of CR 26 mo

1-year RFS - 57%

2-year RFS - 48%

TAR-200 (pretzel)
(SunRISe-1)
Controlled release of gemcitabine in bladder over 2-3 weeks

q3 weeks x 6 mo, then q12 wks x 2 years

Gr 3-4 AE - 30%?

 CR - 70-80%  

Cretostimogene grenadenorepvec
(BOND-003; Phase 3 ongoing)
Adenovirus expressing GM-CSF (T cell response)
(also being studied in combo with pembro)

Similar schedule to BCG

Gr 3-4 AE - 0%

CR - 68.2% at 3 mo, 76% at any time

83% with CR have duration > 12 mo

  
Valrubicin (Valstar) - FDA approved 2000 for BCG-refractory CIS (90 pt study)
Anthracycline chemotherapy

qweek instillation x 6 weeks

(lots of LUTS)

CR - 21%

1-year RFS - only 10% 
56% cystectomy rate

Not a great drug, not used much anymore

  

*in NCCN 2024 guidelines

Intravesical chemotherapy

  • e.g. mitomycin C, gemcitabine
  • See top section for immediate post-operative intravesical chemo
  • Intravesical chemo has little impact on progression, eg use BCG instead for high risk
  • Mitomycin (induction weekly x 6 weeks, then monthly x 3 years for maintenance)
    • To make it more effective:
      • Dehydrate patient (to limit dilution/needing to pee) and use bladder scanner to make sure bladder is empty
      • Alkalinize urine (1.3g Na bicarb at 12h, 3-6h, and 30 min before procedure)
      • Concentrate drug - 40 mg in 20 cc
    • Can cause poor healing when used after TURBT
    • Management of post-MMC cystitis
  • Gemcitabine (induction weekly x 6 weeks, then monthly x 12)
    • 2gm in 100cc, not absorbed and well tolerated
    • Useful as 2nd line after 1st course of BCG
    • Also ~ $30 compared to $1000 for mitomycin
  • Doublet gemcitabine/docetaxel for BCG-resistant disease

 

author: admin | last edited: Aug. 4, 2024, 4:44 p.m. | pk: 177

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