Bladder Cancer

Types:

• Urothelial Carcinoma (transitional cell) (90%)

  • Risk Factors:

    • occupational exposures (dye manufacturers, rubber aluminum factories), smoking

• SCC of the bladder (5%)

  • Associated with chronic inflammation (schistosoma, chronic UTI, chronic foley use)

  • Treatment: Surgery

• Adenocarcinoma of bladder (2%)

  • Treatment: Cystectomy

• Small Cell Bladder Cancer (1%)

  • Treatment: Cisplatin + Etoposide (like regimen for SCLC) → RT or cystectomy

• Plasmacytoid:

  • Associated with CDH1 gene mutation

Diagnosis:

• Cystoscopy with biopsy. Once confirmed, needs TURBT (Transurethral resection of bladder tumor) 

  • Ensure muscle is present in the biopsy specimen. If no muscle: Repeat TURBT

• PET/CT to ensure no distant metastases

Staging:

• T2 (invades muscularis propria) determines need for neoadjuvant therapies

Treatment:

Non-Muscle Invasive Bladder Cancer (cTa, cT1, Tis):

• Typically treated by urology, not necessarily med onc

• If muscle is not present in the specimen: repeat TURBT

• Tx: TURBT followed by single dose intravesical mitomycin C or epirubicin

• Risk stratification for Non-Muscle Invasive Bladder Cancer:

Low risk	- Papillary urothelial neoplasm of low malignant potential - Low-grade urothelial carcinoma + (Ta + ≤ 3 cm + Solitary)
Intermediate risk	- Low-grade urothelial carcinoma + (T1 or > 3 cm, or Multifocal or Recurrence within 1 year) - High grade urothelial carcinoma + (Ta + ≤ 3 cm + Solitary)
High risk	- High-grade urothelial carcinoma + (T1 or > 3 cm, or Multifocal or CIS) - Very high-risk features (any of the following): BCG unresponsive Variant histologies Lymphovascular invasion Prostatic urethral invasion

• Treatment based on risk stratification:

  • Low risk:

    • Followed by surveillance

  • Intermediate Risk:

    • Intravesicular Therapy vs. Surveillance

  • High risk:

    • Very High Risk: Cystectomy preferred over BCG

    • No very high risk features: weekly intravesical BCG x6 doses

      • If CR (negative cytology, no residual cancer):

        • maintenance BCG up to 3 years

      • If no CR (BCG unresponsive/intolerant):

        • Cystectomy (preferred)

        • Pembrolizumab (Keynote-057): if unwilling to undergo surgery

        • Intravesicular chemo: Valrubicin, docetaxel, mitomycin, gemcitabine

        • Nadafaragene firadenovec-vncg

        • Nogapendekin alfa inbakicept-pmln

      • If recurrence of non-invasive bladder tumor:

        • Treatment would be based on new tumor’s AUA risk group

          
          

Muscle Invasive Bladder Cancer:

Stage II (cT2, N0) - Stage IIIA (up to T1-T4a and N1)

• If cystectomy candidate:

  • Need to ask if the patient is “cisplatin eligible?”

    • Galsky criteria for cisplatin ineligible:

      • CrCl <50-60

      • NYHA 3-4

      • ECOG 3-4

      • Grade 2+ neuropathies

      • Grade 2+ ototoxicity

  • If “cisplatin eligible”: neoadjuvant chemo → cystectomy +/- adjuvant nivolumab

    • Neoadjuvant ddMVAC (dose-dense Methotrexate, Vinblastine, Doxorubicin, Cisplatin) prefered over Cis/Gem, but more toxic (VESPER)

    • Neoadjuvant Cis/Gem + Durva (NIAGARA)

    • Consider adjuvant Nivolumab/Pembro x1 year

      • If upstaged to T3/4, N+ or residual disease

  • If “cisplatin ineligible”: upfront cystectomy

• If not cystectomy candidate:

  • TMT (Trimodal therapy): Maximal TURBT followed by chemo-RT

  • Can consider chemo-RT if:

    • <T4

    • “Not next to tubes” (ureters or urethra)- not at UJV or bladder base

    • Not multiple tumors

  • Chemo-RT options:

    • High-Dose Cisplatin

    • 5-FU + Mitomycin

    • Gemcitabine

  • If not candidate for cystectomy or definitive chemoRT

    • RT or TURBT

Stage IIIB (T1-T4, N2, N3 and M0)

• Downstaging systemic therapy:

  • If CR/PR: followed by cystectomy or chemo-RT

  • If no response/progression: treat as metastatic disease

• Concurrent chemo-RT:

  • If PR: consider BCG, surgical consolidation, treat as metastatic disease

  • If progression: treat as metastatic disease

Metastatic Bladder Cancer:

• Preferred: Pembro + Enfortumab Vedotin (EV)

  • EV side effects: Dermatologic side effects, peripheral neuropathies, hyperglycemia, ocular side effects, pneumonitis/ILD, myelosuppression.

  • EV needs eye exam prior to starting and monitoring for DKA.

• Other options:

  • Gem + Cis

  • ddMVAC

  • Gem + Cis + Nivo followed by nivolumab maintenance

  • If not cisplatin eligible:

    • Gem

    • Gem + Carbo

    • Gem + Carbo → avelumab

    • Gem + Paclitaxel

    • Pembrolizumab

    • Atezolizumab

• If SD or CR after chemotherapy: adjuvant avelumab (JAVELIN Bladder 100)

• Later Line options:

  • Pembrolizumab: preferred post-platinum

  • Enfortumab vedotin: after IO, if not received previously

  • Chemotherapy: Gem/Cis, Gem/Carbo, ddMVAC

  • Erdafitinib: if FGFR mutation present

    • Side effects: hyperphosphatemia, hyponatremia, and retinal pigment epithelial detachment (needs baseline ophtho evaluation → monthly for first 4 months → q3 months thereafter. 

  • Sacituzumab govitecan (TROPHY-U-01)

  • Disatamab Vedotin (anti-HER2 with MMAE taxane payload)

  • Fam-trastuzumab deruxtecan-nxki (HER2 positive, IHC 3+)

Urachal Cancer

• If localized: Partial or complete cystectomy with en bloc resection of urachal ligament with umbilicus and LN dissection