Most common urinary cancer

• 4th leading cause of cancer death in males (lung, prostate, colon, bladder)
• > 90% are urothelial carcinoma (UC) (transitional cell).
  • Risk factors: Smoking, chemicals (aniline dye - textile/dye/leather workers), chronic cystitis, radiation, cyclophosphamide (acrolein → hemorrhagic cystitis - reduce by co-administering mesna), genetic syndromes (Lynch, Li Fraumeni, etc)
  • SCC (5%) a/w schistosoma in Middle East/Africa, chronic inflammation (indwelling catheters) in Western countries
  • Adenocarcinoma (2%) a/w bladder exstrophy
  • Histologic variants
  • Thought to arise from basal layer (CIS, MIBC, SCC) or intermediate layer (NMIBC) of urothelium
• Metastasizes to: pelvic LN, liver (38%), lung (36%), bone.
• Secondary cancers include melanoma, colon, prostate, lung, breast

Staging:

• 75% of UC are non-muscle invasive at presentation. 
  • 20% of NMIBC progress to muscle-invasive disease; 50% of high-risk NMIBC progress to MIBC
• Do bimanual exam after TURBT for staging
  • Palpable mass = T3b disease; fixed palpable mass = concern for T4b disease/invasion of pelvic side wall

• 2004 WHO/ISUP grading system
• c - clinical; p - pathological; y - post chemo/radiation
• Tumors in a diverticulum cannot be T2 (no muscle layer in diverticulum)
• Perivesical lymph node = regional lymph node
• ^T1a/b (invasion of muscularis mucosae-vascular plexus) and T1e/m (micro vs macro invasion) substaging are used though not in guidelines yet.
• *Invasion of the prostate
  • Direct invasion through the bladder into the prostatic stroma = T4a bladder cancer
  • Invasion through the prostatic urethra = T2 urethral cancer

Presenting symptoms

• Painless hematuria
  • Bladder cancer found in 13-35% of gross hematuria and 0.5-10% of microscopic hematuria
• Irritative symptoms (dysuria, frequency) a/w CIS
  • 80% of CIS patients presented with irritative voiding symptoms

Diagnosis: Work up with cystoscopy + biopsy, urine cytology.

• UroVysion/FISH - sent on urine cytology; detects chromosome aberrations (3, 7, 17) a/w bladder cancer

Workup: 

• CBC, BMP, LFTs
• CT A/P with contrast
  • MRI > CT before TURBT if muscle-invasive disease suspected; assess extravesical urothelium
  • Hydronephrosis is independent predictor of worse prognosis (suggests presence of extravesical disease)
• Chest imaging (CXR or CT)
• Bone scan only if elevated alk phos or bone pain

TURBT (Transurethral Resection of Bladder Tumors)

• Resect enough to determine depth of invasion
  • **hide**CIS most likely to be found at prostatic urethra near veru
  • **hide**T1a usually papillary on stalk; nodular or sessile → suspicion for muscle invasion
• Perform EUA (exam under anesthesia/bimanual exam) to detect presence of cT3b or cT4 disease
• Imaging to increase cancer detection:
  • HALA (blue light fluorescence of porphyrins 5-ALA in malignant cells) (96% detection vs 77%)
  • Narrow band imaging (shows vascularity; doesn't require instillation)
• Caution:
  • Obturator reflex (leg adduction) can force resectoscope -> bladder perforation.
    • Avoid bladder overdistention (closer to obturator nerve).
    • Bipolar cautery reduces risk of electrical conduction in water -> obturator reflex
    • Paralyze patient during anesthesia
  • Use care in diverticulum (no muscle layer, can perf). Avoid extensive cauterization near the UOS (stricture). OK to TURP at the same time (no seeding)
• Complete resection at time of diagnosis improves survival in patients after radical cystectomy (benefit to aggressive TUR)
• 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
• Surveillance cystoscopy 3 months after TURBT

 Most important risk factor for progression - grade, not stage

Non-muscle invasive (NMIBC)

Intravesical therapy

 Management of variant histologies

Muscle-invasive (MIBC)

Treatment options

• Radical cystectomy vs trimodal therapy (TMT)/bladder preservation (TJG presentation)
  • TMT outcomes improving over last 30 years since introduction in 1980s - cystectomy rates decreased from 37% to 15% (MGH 2017)
  • 2023 Lancet Oncology - TMT outcomes equivalent to RC
    • All patients had - unifocal tumor < 7 cm, no or unilateral hydro, no extensive/multifocal CIS
    • TMT salvage cystectomy rate 13%
    • RC - 90-day mortality rate 2.5%
    • 5-year metastasis free survival: 74% RC vs 75% TMT
    • 5-year overall survival: 66% RC vs 73% TMT
    • 5-year cancer-specific survival: 81% RC vs 83-85% TMT
    • 5-year disease-free survival: 73% RC vs 74% TMT
  • No RCTs to compare the two (2007 SPARE trial could not recruit; equipoise issues (pts who want radiation don't want to be randomized to cystectomy)
• Overall outcomes
  • RC 
    • 10-year overall survival 35%
    • 10-year disease-specific survival 58%
  • TMT (pooled RTOG trials 2014)
    • 5-year overall survival - 57%; 10-year overall survival - 36%
    • 5-year disease-specific survival - 71%, 10-year disease-specific survival - 65%
• Should not offer radiation therapy alone
• Untreated MIBC (2019 Swedish study) - median time to any-cause death 9 mo (vs 42 mo if treated); 80% dead at 18 mo.
  • At 6 mo after diagnosis, 38% had metastasis and 41% had died of cancer.
  • 5-year overall survival rate 5% if untreated (vs 48% if treated).

Radical cystectomy + BPLND

• Indications: muscle-invasive T2-T4a, N0 M0 disease
  • Ideally < 12 weeks between diagnosis and cystectomy
  • Variant histology - high risk of upstaging; consider offering initial radical cystectomy
  • Persistent high-grade T1 on resection or T1 with associated CIS/LVI/variant histology - offer initial RC (mod grade C)
    • Adverse risk factors for progression to MIBC - age > 70, tumor >  cm, CIS. Progression 50% if has all 3
    • CIS - 36% upstaged on cystectomy, 23% to pT2 or higher and 6% node positive
  • BCG unresponsive disease
• Neoadjuvant chemotherapy - superior outcomes (Strong Grade B). 
  • Overall 5-6% overall survival advantage. Strongly consider for cT2N0M0, recommend for cT3-T4N0M0
    • (EORTC phase 3 RCT of MVAC) - 5.5% (50->55.5%) mortality benefit increase at 3 years = 16% reduction in risk of death; median survival time 44 mo vs 37 mo
    • (SWOG 8710 phase 3 RCT of MVAC) - 33% reduction in risk of death; median survival time 77 mo vs 46 mo
      • 38% downstaged to pT0 compared to 15% without NAC, leading to majority of survival benefit (biggest impact for T3a/T4 disease)
    • Gem/cis only really studied in adjuvant setting, but NAC gem/cis commonly accepted due to better side effect profile
      • Best regimen undefined (VESPER trial comparing gem/cis vs ddMVAC)
  • Hard to do adjuvant - surgical deconditioning (25-33% unable to receive adjuvant chemo) - but should be offered adjuvant chemo (Strong Grade C)
  • If complete response and no RC afterwards - 64% 5-year survival (generally low-risk tumors)
  • Nearly 50% of patients are ineligible for cisplatin-based NAC (e.g. renal dysfunction, periopheral neuropathy, hearing loss, overall performance status)
    • Should not use carboplatin if cisplatin-ineligible; just resect it
  • Trial of neoadjuvant pembrolizumab showed pT0 status in 42% of patients...
• If urethral margin positive - should do urethrectomy (immediate or delayed)
• Adjuvant therapy
  • If didn't get NAC and are pT3-4 and/or N+ at cystectomy, offer adjuvant cisplatin-based chemo or immunotherapy (Mod Grade C)
  • Adjuvant nivolumab (q2 wks x 1 year) recommended for patients (with or without NAC) who are pT2-4 and/or N+ at cystectomy. (Mod Grade C) Try to initiate within 90d of cystectomy
    • CheckMate274 - Phase 3 RTC for nivolumab; improved disease-free survival. Median DFS - 20.8 mo vs 10.8 mo. % of patients alive and disease-free at 6 mo: 75% vs 60%. Gr 3 AE: 18% vs 7%.
    • Similar trial with atezolizumab (IMvigor010) failed to demonstrate improvement.
    • Similar trial with pembro ongoing (AMBASSADOR)
• Outcomes - node status and tumor stage most powerful surrogate for recurrence and survival after RC - lymph node status and pathological tumor stage (pT0 have 90% 5-year CSS)
  • 25% will have pathologic N+ at time of cystectomy
    • 10-15% of patients who are clinically T1 end up being N+ at cystectomy
  • Recurrence generally happens within 2-3 years after cystectomy

  • 	Survival	Recurrence (MSK nomogram)
    ypT0	5-year cancer-specific survival: 90% (OS ~ 80%)	5-10%
    <= pT1		10%?
    pT2		20%
    pT4		> 50%
    N0	5-year OS: 49-69%	5-year RFS: 56-78%
    N+	5-year OS: 25-38%	> 70% 5-year RFS: 21-42%

Trimodal therapy for bladder preservation (maximal TURBT, chemo, radiation)

• Optimal candidates (NCCN guidelines BL-5) - good bladder function, no extensive/multifocal CIS, solitart tumor < 5-7 cm, no hydronephrosis, no metastatic disease
  • About 10-15% of 'medically operable' MIBC patients meet this criteria
• Maximal TURBT - 'visibly complete' TURBT has higher complete response rates than incomplete TURBT (70% vs 50%)
• Concurrent chemoradiation
  • Chemo - weekly low dose single agent gemcitabine, or 5FU + MMC
  • Radiation - 40 Gy to bladder +/- nodes (23 fractions), + 20 Gy 'tumor boost' (10 fractions) = ~ 7 wks daily EBRT
• RTOG protocol for bladder preservation - two cycles of chemorads, then mid-cycle TURBT. 
  • If persistent disease - recommend cystectomy.
  • If adequate response, then complete chemoradiation
• QoL - about 1/3 worsened, 1/3 stable, 1/3 improved (EU RCT outcomes 2020)
• Recurrence - lifelong surveillance per high-risk NMIBC schedule. 
  • 20% of patients have NMIBC recurrence (manage similarly with TURBT, intravesical therapies)
  • If MIBC recurrence, -> salvage cystectomy

Metastatic bladder cancer

First line

• Cisplatin-based combo chemo (MVAC or gemcitabine/cisplatin plus avelumab maintenance)
  • Cisplatin contraindications - CrCl < 50-60 ml/min (nephrotoxic), hearing loss (ototoxic), neuropathy, NYHA III/IV / poor functional status
    • Carboplatin is more tolerable but less efficacious 
  • MVAC = MTX, vinblastine, doxorubicin (adriamycin), cisplatin
    • > cisplatin single-agent (39 v 12% response rate, 12.5 v 8.2 mo OS)
    • More toxic (leukopenia, mucositis)
    • HD-MVAC higher response rate - 21% vs 9%; survival 9.1 v 8.2 but not significant until 7 yrs
    • ddMVAC is 4 cycles q2 weeks; gem/cis takes longer
  • Gemcitabine/cisplatin most commonly used  - less toxic than MVAC, no diff in response rates (49 v 46%, progression 7.4 mo, survival 13.8 v 14.8 mo). Only 37% needed dose modifications vs 63% in MVAC arm; less neutropenia
• 40-70% will have initial response to chemo, but most will progress - median survival 14 mo, 5-year OS 5-20%
  • For those who respond to chemo, can consider consolidative surgery/cystectomy - possible 5-year OS 30% vs 15%? Or radiation?
• Standard of care also now includes maintenance avelumab if there was no progression on first-line platinum therapy; improved median OS by 7 months (21 vs 14 mo)
• If cisplatin-ineligible
  • If low PD-1 expression: Gem/carboplatin + avelumab maintenance
  • Pembrolizumab
• FDA approved 12/2023 - enfortumab-vedotin + pembro first-line for both locally advanced and metastatic urothelial carcinoma, instead of second line after gem/cis
  • EV: nectin-4 antibody delivering MMAE (microtubule inhibitor) payload
    • Toxicity: neuropathy
  • Survival benefit compared to gem/cis: 
    • Median OS: 31.5 mo vs 16.1 mo for EV/pembro vs gem/cis
    • Median PFS: 12.5 mo vs 6.3 mo

Second line

• PDL-1 therapy (eg pembrolizumab, nivolumab, avelumab)
  • Lots of severe side effects...severe rash, colitis, pneumonitis, myocarditis, diabetes, thyroid dysunction...may require long-term steroids. 1% risk of death
  • Atezolizumab withdrawn - did not improve overall survival
• Erdafitinib - only if patient has susceptible FGFR mutation (FGFR3 mutations a/w more low grade/favorable tumors?)
  • Targeted by erdafitinib
• Enfortumab vedotin - anti-nectin 4 antibody linked with microtubule inhibitor
  • Also useful if has failed chemo + pembro - 4 month improvement in survival, 12% complete response rate

Molecular subtypes

• "Non-invasive" pathway a/w mutations in oncogenes FGFR3, PIK3CA, loss of heterozygosity on chromosome 9q
• "Invasive" pathway a/w mutations in tumor suppressor genes TP53, RB1
  • CIS is in this pathway/behaves more similar to T2
• Luminal subtype a/w p53 expression, favorable prognosis but doesn't respond much to NAC
• Basal subtype with poor prognosis but good response to NAC

Outcomes