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Muscle Invasive Bladder Cancer (AUA management algorithm)

Considerations

• Mortality rate 85% at 2yrs if untreated
• No need for reTURBT if T2+
• Labs: check CBC, CMP, AlkPhos
• Upper tract imaging (CTU/MRU): should have already been obtained at time of bladder tumor workup
• Chest imaging: consider in patients at risk for metastasis
• Bone scan: indicated for bone pain, elevated AlkPhos, or high risk for bone mets, can also evaluate with FDG-PET/CT
• Brain imaging: indicated for CNS symptoms or high risk for brain mets, brain MRI is best test
• PET/CT: not recommended for initial staging, 80% accuracy for diagnosis LN metastases
• Planning: determine ability to remove bladder, presence of LN mets, presence of hydro, presence of UT disease, local extent of disease, presence of distant mets
• Gold standard: neoadjuvant chemotherapy followed by radical cystectomy

Metastatic Bladder Cancer

Staging	Chemotherapy	Cystectomy	XRT
N1 M0	Cisplatin-based regimen Enfortumab vedotin + pembrolizumab (if cisplatin-ineligible)	Consider if good response to chemotherapy (potential for cure)	Only if not candidate for cystectomy
T4b or N2-3, M0	Enfortumab vedotin + pembrolizumab		Symptom management (palliative)
M1		Very select patients

• Response rates: 70% but median survival 14 months and 5yr survival 5-20%
• MSKCC data: assess whether Karnofsky < 80% and/or visceral mets - median survival 33mo, 13mo, 9mo for presence of 0, 1, or 2 factors
• Chemo/immuno options: EV-Pembro now recommended for metastatic bladder cancer, cisplatin-based regimen recommended if eligible and nodal metastasis only
• Cystectomy: consider if adequate response to chemotherapy and potential for cure or if needed for symptom palliation

Drug	Class	Common side effects	Less common side effects	Monitoring
Pembrolizumab	PD-1 inhibitor	Fatigue MSK pain Pruritus GI distress Cough/dyspnea Peripheral edema	Pneumonitis Colitis Hepatitis Thyroiditis Nephritis	BMP, LFT, thyroid
Nivolumab
Avelumab	PD-L1 inhibitor
Atezolizumab
Erdafitinib	FGFR inhibitor	Abnormal labs Stomatitis Dry mouth/eye GI distress Dysgeusia Onycholysis	Ocular disorders Hyperphosphatemia	Ophtho exams Phosphate measurements
Enfortumab vedotin	Microtubule disruptor MMAE binds nectin-4 receptor	Abnormal labs Dysgeusia GI distress Alopecia	Hyperglycemia Ocular disorders Peripheral neuropathy	Ophto exams Glucose checks

Cystectomy

Cystectomy considerations

• Timing: perform 6-8 weeks after neoadjuvant therapy (no later than 12 weeks), otherwise within 3mo diagnosis if no NAC
• Repeat imaging prior to surgery to confirm no metastases
• Optimize performance status: smoking cessation (8 weeks prior), nutrition optimization
• Perform preoperative stoma marking with patient standing and sitting
• Preop medications: no proven benefit for bowel prep, give alvimopan (entereg) 30-90min prior, give IV antibiotics within 1hr surgical incision, give heparin prior to surgical incision and start SCDs
• Pelvic LND: metastases present in 25% at time of cystectomy, 70-80% develop recurrence as opposed to 30% with node-negative disease, increased sensitivity for node-positive disease with removal of greater number of nodes
• Intraop findings of concern: do not complete cystectomy if unresectable nodal disease, evidence of extensive periureteral disease, fixed bladder to sidewall, or tumor invading rectosigmoid colon - aborting cystectomy has poor prognosis
• Positive ureteral margin: 6-8%, no clear indication for frozen examination, increased risk for upper tract recurrence
• Male urethrectomy: consider if widespread CiS of prostatic urethra or stromal invasion, female urethrectomy if T4 disease
• Female GU involvement: reported in ~7.5%, 85% had recurrence within 5yr
• Postop anticoagulation x4 weeks reduces VTE risk by 82% (4.6 vs 0.8%)
• Complications: ileus (2-32%), infection (5-39%), diversion issues (up to 33%), readmission (10-30%), mortality (3%, 4-6% if > 75yo)

Lymph node dissection

• Packets removed: obturator, internal iliac, and external iliac nodes, extended removes common iliac nodes
• Standard template: common iliac bifurcation superiorly, inguinal ligament inferiorly, bladder medially, genitofemoral nerve laterally
• Extended template: extends proximally to aortic bifurcatoin

Preserving sexual function

• Goal: preserve sexual function if it does not compromise cancer control
• Nerve sparing: can attempt preservation in men and women, urethrectomy decreases potency even with nerve sparing
• Contraindications to vaginal-sparing: T3-4, unfavorable location (bladder neck, trigone, urethra), direct vaginal wall invasion
• Gynecologic organ involvement: rare especially after neoadjuvant chemotherapy, attempt to maximally spare organs, especially ovaries for hormonal benefits (per Bree 2021)
• Seminal vesical sparing contraindicatoins: T3-4, unfavorable location (bladder neck, prostatic urethra, anterior urethra), prostate cancer present
• Erectile dysfunction: common, occurs > 40% even with nerve/prostate sparing

Neoadjuvant Chemotherapy

• Cisplatin-based therapy: current gold standard, options currently ddMVAC or gem/cis
• Cisplatin exclusion criteria: WHO/ECOG > 2, CrCl < 60, Grade 2+ audiometric hearing loss, Grade 2+ peripheral neuropathy, NYHA Class III+ CHF - substitute carboplatin but decreased efficacy
• Benefits: decreases all cause mortality (65% -> 59%, HR=0.75) and cancer-specific mortality (50% -> 35%, HR=0.60) at 8yrs, lengthens median survival (46mo -> 77mo) - 5-6% increased survival at 10yrs, increases pT0 cystectomy rates from 15% to 38% (Grossman 2003)
• Cisplatin side effects: nephrotoxicity, cardiotoxicity, neurotoxicity, ototoxicity
• Cisplatin alternatives: EV-Pembro is now recommended (as of 2026)
• Can consider adjuvant chemotherapy if neoadjuvant not given

Adjuvant therapy

• Chemotherapy: offer if high risk for recurrence (T3-T4, LVI, N+), no prior neoadjuvant chemotherapy, and able to receive chemotherapy, should be cisplatin-based
• XRT: offer if T3-4 and N0-2, improves local control but not overall survival, cannot use for continent diversions due to risk of XRT injury
• Immunotherapy: currently no role

Post-Cystectomy prognosis

• 5yr recurrence rates: ≤ pT1 (10-25%), pT2 (20-30%), pT3 (40-60%), pT4 (50+%), pN1+ (70%)
• Most recurrences within 2-3yrs and are non-curative
• RTOG (from AUA): 5yr survival overall (57%) and disease specific (71%), 10yr survival overall (36%) and disease specific (65%)
• Local recurrence: < 12% patients
• UTUC recurrence: 1-8%, monitor w/ CT q6mo for 2-3yrs postop

Urethral recurrence after cystectomy

• Seen 1-15%, usually within 2yrs but ~10% after 5yrs
• Can occur either from local extension or from field effect
• Risk factors: multifocal bladder tumors, CiS, hx NMIBC, prostatic urothelial carcinoma (males), positive urethral margin, and cutaneous diversion, bladder neck involvement (females)
• Orthotopic neobladder: may have protective effect due to continued urethral exposure to urine
• Prophylactic urethrectomy indications: positive intraoperative urethral margin, gross urethral involvement, prostatic ductal/stromal involvement, female bladder neck tumors
• Urethral washing: check q6-12mo, place catheter/cystoscope to proximal urethra, flush in 20mL and collect at meatus, although ultimate benefit of urethral screening is quesitonable
• Management: urethrectomy, convert neobladder to conduit, CiS only can be treated with intraurethral BCG

Alternatives to Cystectomy

Trimodal therapy

• TURBT + chemo + XRT, considered gold standard of bladder-preserving therapies
• Criteria: unifocal tumor, no CiS, no hydronephrosis, complete resection obtainable, cT2
• Contraindications (high salvage cystectomy rate): unresectable tumor, T3-4, multifocal CiS, extensive CiS, hydronephrosis secondary to cancer
• During chemoXRT, evaluate with cystoscopy and imaging, consider cystectomy if poor response
• Salvage cystectomy: required in 10-30%, indicated for recurrence/progression 11-19%, may be more difficult due to pelvic XRT and increased patient frailty
• Maintaining selection criteria increases 5yr survival 53% -> 75% and salvage cystectomy 29% -> 16%
• 5yr cancer-specific survival similar, but trimodal patients tend to be healthier, and higher rates of local recurrence (43% vs < 12%)
• Patients report better sexual function and better body image perception

Partial cystectomy

• Criteria (requires all): solitary cancer, no CiS, negative random bladder biopsies, no prior bladder tumors, no prostatic invasion, adequate expected bladder capacity, able to obtain negative margins
• Recommendations: give NAC, perform bilateral PLND, reimplant ureter if orifice involved, consider adjuvant chemo if nodal metastasis
• Risks: potential for seeding tract if SPT placed, recurrence in 32% (usually NMIBC), 15% need radical cystectomy, 5yr cancer-specific survival 68%
• Non-urothelial: can be used for pheochromocytoma (paraganglioma), urachal cancer, and local invasion of non-bladder cancer

Other alternatives

• XRT alone: 5yr survival 35-40%, beneficial for frail patients (poor surgical candidates)
• XRT + chemo (5FU, mitomycin, cisplatin, gemcitabine): improved relapse and salvage cystectomy rates compared to XRT alone, disease-free survival 67% vs 54% at 2yrs, HR 0.68
• XRT complications: early GI toxicity (68%), early GU toxicity (84%), late GI toxicity (27%), late GU toxicity (29%)
• Maximal TURBT + negative reTURBT: up to 82% survival at 5yrs
• Chemotherapy without cystectomy: high risk for recurrence