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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 (not carboplatin) First line if no contraindications	Consider if good response to chemotherapy (potential for cure)	Only if not candidate for cystectomy
T4b or N2-3, M0			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
• First line: ddMVAC or gem/cis
• Progression after first line: pembrolizumab, nivolumab, avelumab, erdafitinib
• Progression after second line: erdafitinib, enfortumab vedotin
• Carboplatin: can consider if not cisplatin-eligible, but less efficacious (only applies to M1, do not give carboplatin for M0)
• Cystectomy: consider if adequate response to chemotherapy and potential for cure or if needed for symptom palliation

Ophtho exams
Phosphate measurements

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
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: carboplatin not considered adequate substitute, recommended to have up-front cystectomy
• 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