Muscle-Invasive Bladder Cancer

See 2024 AUA MIBC Guideline Notes

See 2019 CUA MIBC Guideline Notes

Presentation

• At the time of initial bladder cancer diagnosis
  • ≈75-80% of patients will present with non-muscle invasive bladder cancer (NMIBC)
  • ≈20-25% of patients will present with muscle-invasive bladder cancer (MIBC)
• ≈20% of patients initially diagnosed with NMIBC will progress to MIBC
  • ≈50% or more patients with high-risk NMIBC can progress to invasive disease.
  • Patients who initially present with NMIBC and progress to MIBC have been found to have a worse prognosis than patients who initially present with MIBC

Prognosis

• Highly lethal; 85% mortality at 2 years if untreated
  • Overall prognosis of patients with MIBC has not changed in the last 30 years

Diagnosis and Evaluation

UrologySchool.com Summary★

• History and Physical exam
  • Exam under anesthesia at time of TURBT for a suspected invasive cancer
• Imaging (2):
  1. Regional: CT abdomen/pelvis
  2. Distant: Chest (CT or CXR)
• Labs (3):
  1. CBC
  2. Liver function tests
  3. Renal function
• Other (1):
  1. TURBT pathology

History and physical exam

• Examination under anesthesia
  • Performed at the time of TURBT for a suspected invasive cancer
  • Provides information for the clinical staging and resectability of the primary tumor at surgery.
    • This information contributes to the overall determination of clinical stage and assessment of potential benefit of neoadjuvant chemotherapy (NAC).
      • Presence of a large/3-dimensional, residual mass after TURBT (cT3b), invasion of adjacent structures (cT4a), or fixation (cT4b) imply locally advanced clinical stage.

Imaging

• Goals of imaging in MIBC are to determine:
  1. Feasibility and safety of removing of the bladder
  2. Presence of hydronephrosis
  3. Presence of upper tract disease
  4. Local extent of the disease
  5. Presence of pelvic or retroperitoneal lymph node metastases
  6. Visceral/distant metastatic sites
• Regional
  • Cross-sectional imaging of the abdomen/pelvis with IV contrast (if not contraindicated)
• Metastasis
  • Chest (CT or CXR)
    • Prior smokers may benefit from a chest CT; non-smokers should have a minimum of a chest x-ray (with posterior-anterior and lateral images).****Non-smokers also may benefit from CT imaging to evaluate for metastatic cancer.
  • Bone scan
    • Indications (2):
      1. Elevated alkaline phosphatase
      2. Presence of bone pain symptoms
  • PET imaging
    • Indications (2):
      1. Abnormal chest, abdominal, or pelvic imaging that requires further evaluation
      2. Biopsy of a suspicious lymph node is not feasible

Laboratory

• CBC, liver function tests, and renal function
  • CBC: provides information regarding anemia and possible occult infection
  • Liver function tests and renal function: choice of urinary diversion in patients undergoing cystectomy is greatly influenced by metabolic abnormalities, such as acidosis or renal or hepatic insufficiency, and abnormal laboratory values may impact the ability to administer chemotherapy.
    • Other than alkaline phosphatase, liver function tests not further specified.
      • Liver function tests typically include[1]:
        • Alanine transaminase (ALT)
        • Aspartate transaminase (AST)
        • Alkaline phosphatase (ALP)
        • Gamma-glutamyl transferase (GGT)
        • Serum bilirubin
        • Prothrombin time (PT)
        • International normalized ratio (INR)
        • Total protein
        • Albumin

Other

• TURBT pathology
  • Provides information on clinical staging, in addition to EUA
  • If variant histology (e.g., micropapillary, nested, plasmacytoid, neuroendocrine, sarcomatoid, extensive squamous or glandular differentiation) is suspected OR if muscle invasion is equivocal, an experienced genitourinary pathologist should review the pathology
    • Pathologic re-review of cystectomy specimens by experienced genitourinary pathologists may identify variants that alter treatment in up to 33% of patients

Management

Patient counseling

• For patients with newly diagnosed MIBC, curative treatment options should be discussed based on both patient comorbidity and tumor characteristics. Patient evaluation should be completed using a multidisciplinary approach.
• Prior to treatment, patients should be counselled regarding complications and the implications of treatment on quality of life (e.g., impact on continence, sexual function, fertility, bowel dysfunction, metabolic problems).
  • Patients with
    • Ileal conduit urinary diversion require external appliances and have risks of leakage or stomal complications.
    • Continent cutaneous reservoirs require self-catheterization for the rest of their lives and have risks of incontinence via their stoma, stricture, pouchitis, pouch stones, and metabolic derangements.
    • Neobladders have risks of incontinence (especially night-time), bladder neck contractures, voiding dysfunction with retention, and fistula formation
  • Sexual dysfunction, metabolic and nutritional issues can also result from urinary diversions (Recall LSD ORGASMIC from Complications of Urinary Diversion notes)

Options

• Standard treatment of MIBC (clinical T2-T4a, N0, M0 disease) regardless of histologic subtype* is radical cystectomy (RC) and bilateral PLND
  • Timing of neoadjuvant chemotherapy (NAC) and/or radiation therapy can vary by histology
    • If histology urothelial or neuroendocrine, standard treatment is NAC + RC
      • Pure neuroendocrine variants of bladder cancer are relatively rare but highly aggressive, and they typically present at high pathologic stages or with metastatic disease.
    • If histology small cell, standard treatment is initial chemotherapy followed by radiation or cystectomy as consolidation, if there is no metastatic disease§
    • If pure non-urothelial histologic subtypes (squamous, adenocarcinoma, sarcomatoid): perioperative chemotherapy is not routinely recommended as they are perceived to generally be chemo-resistant.★
• Alternatives
  • Multi-modal/Trimodal Therapy
  • Partial cystectomy and chemotherapy
  • Chemotherapy alone
  • Radiation alone

Neoadjuvant/adjuvant chemotherapy

Neoadjuvant

Advantages

1. Better tolerated before surgery, rather than after surgery when patients may experience a delay in chemotherapy administration because of complications or debilitation
2. Patients who present with micrometastatic disease will receive therapy in a more timely fashion when their burden of disease is potentially low
3. Downstage bulky and locally advanced tumors, allowing for a higher likelihood for negative surgical margins that are a known predictor of local recurrence following cystectomy
4. Assess each individual’s response to therapy

Disadvantages

1. Delay in definitive local therapy for patients who do not respond to chemotherapy and thus experience disease progression
2. NAC-related toxicity (risk of venous thromboembolism, mortality)
3. Non-selective nature of NAC

• NAC does not increase perioperative morbidity or complication rates

Evidence

• 2 large phase III clinical trials have demonstrated an OS benefit with the use of NAC prior to RC
  • SWOG 8710
    • Population: 317 patients with cT2-T4aN0M0 MIBC
    • Randomized to 3 cycles of neoadjuvant MVAC (methotrexate, vinblastine, adriamycin [doxorubicin], cisplatin) + RC vs. RC alone
    • Results:
      • Absolute risk difference for pT0 status at the time of cystectomy: 23% with NAC (38% chemotherapy vs. 15% controls)
        • Patients who were downstaged to pT0 achieved excellent outcomes with 80% alive at 5 years compared to 40% of patients with residual disease
      • Absolute benefit median OS: 31 months (77 months MVAC vs. 46 months in RC-only group)
      • Absolute benefit 5-year OS: 14% (57% MVAC vs. 43% in RC-only arm). However, the survival results failed to reach statistical significance (P = .06)
    • Grossman, H. Barton, et al. "Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer." New England Journal of Medicine 349.9 (2003): 859-866.
  • BA06 30894
    • Population: 976 patients with MIBC
    • Randomized to neoadjuvant CMV vs. cystectomy alone
    • International Collaboration of Trialists. "International phase III trial assessing neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: long-term results of the BA06 30894 trial." Journal of Clinical Oncology 29.16 (2011): 2171.
• 2005 meta-analysis combining individual patient data from 9 trials (these 2 trials with 9 phase II trials) involving 3005 patients comparing neoadjuvant chemotherapy plus local treatment with the same local treatment alone found that neoadjuvant chemotherapy was associated with improved:
  • 5-year OS: absolute benefit 5%
  • 5-year DFS: absolute benefit 9%
  • Pathologic complete response (pT0) rate of 30-40% compared to 15% (SWOG trial results) without NAC
  • Advanced Bladder Cancer (ABC) Meta-analysis Collaboration. “Neoadjuvant chemotherapy in invasive bladder cancer: update of a systematic review and meta-analysis of individual patient data advanced bladder cancer (ABC) meta-analysis collaboration.” Eur Urol. 2005 Aug;48(2):202-5; discussion 205-6. Epub 2005 Apr 21.
• Gemcitabine-cisplatin (GC) is a combination frequently used for NAC in MIBC due to relatively lower risk of toxicity, despite level 1 evidence for MVAC and CMV only
  • No completed prospective randomized trials have compared GC to other regimens as NAC for MIBC. Several retrospective cohort studies suggest that there may not be a significant difference in outcome between GC and MVAC
• The best regimen and duration for cisplatin-based NAC remains undefined; most studies have evaluated 3-4 cycles of preoperative chemotherapy over about 3 months

Indications

AUA

• 2020 AUA Muscle-Invasive Bladder Cancer Guidelines
  • Prior to cystectomy, cisplatin-based NAC should be offered to eligible radical cystectomy patients, utilizing a multidisciplinary approach

CUA

• 2019 CUA Muscle-Invasive Bladder Cancer Guidelines
  • All eligible patients with cT2-T4a N0 M0 urothelial carcinoma of the bladder should be encouraged to receive cisplatin-based combination chemotherapy (Gemcitabine/Cisplatin (GC), MVAC or dd-MVAC) as neoadjuvant therapy (NAC) prior to radical local therapy

Contraindications

• If ineligible for cisplatin-based NAC, patients should proceed to definitive locoregional therapy (AUA/CUA)**Carboplatin-based neoadjuvant chemotherapy should not be used for clinically resectable stage cT2-T4aN0 bladder cancer

AUA

• 2020 AUA Muscle-Invasive Bladder Cancer Guidelines
  1. eGFR < 60ml/min
  2. Heart failure (NYHA Class > 2)
  3. ≥Grade 2 hearing loss (grading based on Common Terminology Criteria for Adverse Events version 4.0)
  4. ≥Grade 2 neuropathy(grading based on Common Terminology Criteria for Adverse Events version 4.0)
  5. Reduced performance status (ECOG ≥2 or Karnofsky performance status ≤60-70%)

CUA

• 2019 CUA Muscle-Invasive Bladder Cancer Guidelines (HE 2 NICE)
  • Absolute (6):
    1. ≥Grade 2 Hearing loss (grading based on Common Terminology Criteria for Adverse Events version 4.0)
    2. eGFR ≤ 50 ml/min/1.73m2
    3. ≥Grade 2 Neuropathy (grading based on Common Terminology Criteria for Adverse Events version 4.0)
    4. Untreated Infection
    5. Cardiac failure (NYHA Class > 2)
    6. Eastern Cooperative Group (ECOG) ≥2
  • Relative:
    1. eGFR 50-60 ml/min/1.73m2
    2. History of recurrent infection and concomitant immunosuppression

Drugs and Dosages

• The best regimen and duration for cisplatin-based NAC remains undefined
  • No prospective randomized trials have compared gemcitabine and cisplatin to MVAC
    • Retrospective studies have suggested that there is no difference between the regimens in terms of survival.
  • A retrospective study found that patients who did not receive cisplatin-based chemotherapy or fewer than 3 cycles of chemotherapy had worse outcomes, compared to those that who received ≥ 3 cycles of cisplatin-based NAC, either GC or MVAC regimen at standard dose[2]

Timing of radical cystectomy after NAC

• Radical cystectomy is recommended as soon as possible following completion of and recovery from NAC, ideally within 12 weeks (CUA: 4-6 weeks after NAC and no more than 10 weeks), following completion of chemotherapy, unless medically inadvisable.
  • Patients must be medically fit to undergo cystectomy.
  • Optimal timing to proceed with cystectomy after chemotherapy has not been defined.
    • Observational studies that suggest that outcomes may be worse if cystectomy is delayed more than 12 weeks after the completion of chemotherapy.

Adverse events

• Cisplatin eligibility is a major determinant of candidacy for NAC

• Adverse events related to cisplatin (4):
  1. Nephrotoxicity
  2. Ototoxicity
  3. Neurotoxicity
  4. Diminished cardiac function
  • These preclude 30-50% of MIBC patients from safe receipt of cisplatin-based chemotherapy
• No validated predictive factors or clinical characteristics (including age) associated with an increased or decreased probability of response and benefit using cisplatin-based NAC
  • The decision regarding eligibility for cisplatin-based NAC should be based on comorbidities and performance status, including cardiac status and presence of peripheral neuropathy, hearing loss, and renal dysfunction

Histological considerations

• NAC is primarily derived in the urothelial carcinoma setting
  • Secondary analysis of SWOG 8710 found that patients with mixed tumours (squamous and glandular differentiation) derived greater benefit (HR 0.46) from neoadjuvant MVAC than patients with pure urothelial carcinoma (HR 0.9), compared with cystectomy§
• Lack of robust data supporting NAC in pure non-urothelial histologies
  • Exceptions are pure small cell or pure neuroendocrine carcinoma of the bladder where NAC is the mainstay of treatment
  • [CUA Guidelines do not support NAC in pure non-urothelial histology, other than noted exceptions]

Adjuvant

• Patients with pT3-T4 or N+ disease are at high risk for failure following cystectomy and can be offered adjuvant chemotherapy to treat micrometastatic disease and to improve survival

Advantages

1. Allows for immediate local treatment with cystectomy and avoids any delay in treatment in patients with chemotherapy-resistant tumors
2. Avoids overtreatment; the availability of final pathology also allows clinicians to select patients at the highest risk for failure who are most likely to benefit, while sparing those who are less likely to progress from the side effects of systemic chemotherapy.

Disadvantages

• Often difficult or impossible for patients to undergo systemic therapy following cystectomy secondary to surgical deconditioning, deteriorating renal function, or perioperative complications
  • ≈24-52% of patients have renal function deterioration that makes them ineligible to receive AC postoperatively depending on the criteria used.
  • Postoperative complications may exclude ≈30% of patients who may have been eligible from receiving AC postoperatively

Evidence

• No single phase III trial has demonstrated an overall survival benefit with AC compared to observation
• 2014 meta-analysis of 9 trials involving 945 patients comparing AC to standard of care found a 9% absolute survival benefit at 3 years. However, there were major deficiencies in the trials included such as small sample sizes, early closure of trials, limitations in statistical analysis, and differences in the way disease-free survival was defined.
  • Leow, Jeffrey J., et al. "Adjuvant chemotherapy for invasive bladder cancer: a 2013 updated systematic review and meta-analysis of randomized trials." European urology 66.1 (2014): 42-54.

Indications

AUA

• 2020 AUA Muscle-Invasive Bladder Cancer Guidelines
  • Eligible patients who have not received cisplatin-based NAC and have non-organ confined (pT3/T4and/or N+) disease at cystectomy should be offered adjuvant cisplatin-based chemotherapy (same as CUA)

NAC vs. Adjuvant Chemotherapy

• The available evidence suggests perioperative chemotherapy does confer a survival benefit for bladder cancer patients, with stronger evidence available in the neoadjuvant approach. The optimal approach and benefit to systemic chemotherapy in the adjuvant setting remains incompletely defined, and may remain unanswered based on the difficulty with patient accrual in past trials

Neoadjuvant/Adjuvant Immunotherapy

Neoadjuvant

• PURE-01 (neoadjuvant pembrolizumab)
  • Phase II trial evaluated neoadjuvant pembrolizumab in 50 patients undergoing RC for MIBC and found that 42% of patients achieved pT0§

Adjuvant

CheckMate 274 (adjuvant nivolumab)

• Population: 709 patients with high risk of recurrence after radical surgery for muscle-invasive urothelial carcinoma of the bladder, ureter, or renal pelvis, with or without neoadjuvant cisplatin-based therapy
  • High risk defined as
    • Pathological stage pT3, pT4a, or pN+ and patient not eligible for or declined adjuvant cisplatin-based combination therapy for patients without previous neoadjuvant cisplatin-based chemotherapy
    • Pathological stage ypT2 to ypT4a or pyN+ for patients who received neoadjuvant cisplatin
    • Enrollment of patients with upper tract urothelial carcinoma capped at approximately 20%
• Randomized 1:1 to nivolumab (240 mg intravenously) or placebo every 2 weeks for up to 1 year
• Outcomes:
  • Primary: disease-free survival
    • Among all the patients (intention-to-treat population)
    • Among patients with a tumor programmed death ligand 1 (PD-L1) expression level of ≥1%
  • Secondary: survival free from recurrence outside the urothelial tract, overall survival, and disease-specific survival
• Results
  • Median follow-up: ≈20 months
  • Primary outcome: disease-free survival
    • Disease-free survival benefit: 10 months (21 months nivolumab vs. 11 months placebo)
    • Absolute disease-free survival benefit at 6 months:
      • All patients: 15% (75% adjuvant nivolumab vs. 60% placebo)
      • PD-L1 patients (40% of all patients): 18% (74% adjuvant nivolumab vs. 56% placebo)
    • In patients with upper tract urothelial carcinoma, hazard ratio in favour of placebo
  • Secondary outcomes:
    • Distant metastasis-free survival improved with adjuvant nivolumab in both groups
    • Overall survival and disease-specific survival not reported
    • Adverse events
      • Most common adverse events in nivolumab group: pruritis (23%), fatigue (17%), and diarrhea (17%)
      • Most common adverse events of grade 3 or higher in nivolumab group: elevated serum lipase (5%), elevated serum amylase (4%), diarrhea (1%), colitis (1%), and pneumonitis (1%)
      • 3/351 (1%) treatment-related deaths in nivolumab group, 2 from pneumonitis, 1 from bowel perforation
• Bajorin, Dean F., et al. "Adjuvant nivolumab versus placebo in muscle-invasive urothelial carcinoma." New England Journal of Medicine 384.22 (2021): 2102-2114.

Radical Cystectomy

• See Cystectomy Chapter Notes
• Radical cystectomy with bilateral pelvic lymphadenectomy should be offered for surgically eligible patients with resectable non-metastatic (M0) muscle-invasive bladder cancer.
  • For non-metastatic MIBC, NAC + RC is the standard of treatment
  • Bladder preserving therapy has been associated with decreased survival compared to RC
• When performing a standard radical cystectomy, clinicians should remove the bladder, prostate, and seminal vesicles in males and should remove the bladder and consider removal of adjacent reproductive organs based on individual disease characteristics and need to obtain negative margins
  • Radical cystectomy involves removal of the bladder (cystectomy) along with the organs at highest risk of harboring tumors that extend beyond the bladder.
  • Organ sparing procedures in females should be considered based on disease location and characteristics on an individual basis
    • Considering the overall low incidence of urothelial cancer involvement of the uterus, ovaries, and vagina and the absence of conclusive evidence suggesting a measurable outcome difference in removing these organs, this scrutiny is appropriate.
    • When performing ovarian/uterine sparing procedures in women who do not desire fertility, consideration to salpingectomy should be given to reduce the risk of ovarian cancer.
    • In select women with early-stage disease and a desire to preserve fertility and/or sexual function, organ preservation may be considered as long as complete tumor resection can be achieved.
      • Preoperative counseling should be performed for patients who have invasive cancer at the bladder neck or trigone region in regards to risk of organ sparing surgery.
        • • More emphasis on organ preservation in females compared to 2020 and 2017 MIBC guidelines.

Urethrectomy

• Indications★
  1. All females not receiving neobladder to reduce risk of positive surgical margin or tumor recurrence (different than CUA)
  2. Males with invasive cancer at the apical urethral margin
     • Apical urethral margin assessed with
       • Intra-operative frozen section OR
       • Final pathology of the radical cystectomy specimen
     • Urethrectomy can be performed at the time of cystectomy or delayed

Sexual function preserving procedures

• Should be considered for patients with organ-confined disease and absence of bladder neck, urethra, and prostate (male) involvement.

• Nerve-sparing should be discussed and offered in all patients who desire sexual function preservation and are sexually active, as long as it will not compromise oncologic control.
• Prostate-sparing and prostate-capsule sparing cystectomy in males
  • May be offered to highly select males with negative prostatic urethral and transrectal prostate biopsies in whom fertility and sexual function are important considerations.
  • Nerve sparing procedures in males may offer similar rates of sexual function preservation when compared to prostate-sparing cystectomy.
• Vaginal sparing radical cystectomy in females
  • Can be performed when doing so will not compromise tumor control, such as in the absence of cancer in the trigone or bladder base.
  • Consideration may also be given to preserving the ovaries for hormonal homeostasis, and the anterior vaginal wall and/or uterus may be preserved in the absence of direct tumor extension.

Perioperative surgical management

• Clinicians should attempt to optimize patient performance status in the perioperative setting.
  • Optimizing nutritional status prior to surgery; preoperative carbohydrate loading in order to diminish postoperative insulin resistance
  • Smoking cessation counseling
  • Consider not routinely prescribing a mechanical bowel preparation when only small bowel will be used for urinary tract reconstruction
• Perioperative pharmacologic thromboembolic prophylaxis should be given to patients undergoing radical cystectomy.★
  • Combined mechanical and pharmacologic prophylaxis is recommended.
    • Strong consideration should be given to initiating pharmacologic prophylaxis just prior to induction of anesthesia; however, the risks of bleeding need be weighed against the benefits of prophylaxis in determining the timing of heparin administration.
  • Perioperative coverage with up to 4 weeks of treatment following surgery may be beneficial.
• μ-opioid antagonist therapy should be used to accelerate gastrointestinal recovery, unless contraindicated.
  • μ-opioid antagonist therapies are contraindicated in patients who have taken opioids for ≥ 1 week prior to surgery
• Patients should receive detailed teaching regarding care of urinary diversion prior to discharge from the hospital

Urinary diversion

• In patients undergoing radical cystectomy, ileal conduit, continent cutaneous, and orthotopic neobladder urinary diversions should all be discussed.
  • Absolute contraindications to continent diversion (6):★
    1. Insufficient bowel segment length
    2. Inability to perform self-catheterization
       • Due to inadequate motor function or psychological issues
    3. Inadequate renal function (e.g. an eGFR < 45)
       • Increases the risk metabolic abnormalities as a consequence of reabsorption of urine from continent diversions
    4. Inadequate hepatic function
       • Increases the risk metabolic abnormalities as a consequence of reabsorption of urine from continent diversions
    5. Cancer at the urethral margin (specifically for orthotopic neobladder)
    6. Significant urethral stricture disease that is not correctable (specifically for orthotopic neobladder)
• In patients undergoing an orthotopic urinary diversion, a negative urethral margin must be verified
  • Risk cancer developing in the retained urethral is 1-17%, the majority of which occur within the first 2 years after surgery.
  • Risk factors include: tumor multiplicity, papillary pattern, CIS, tumor at the bladder neck, prostatic urethral involvement, and prostatic stromal invasion.
    • Although prostate involvement is the most significant risk factor for cancer in the urethra, it should not preclude orthotopic diversion, provided that intraoperative frozen section analysis of the urethral margin is without evidence of tumor.
  • Preoperative prostatic urethral biopsies have not proved to be as reliable as urethral frozen sections and should not exclude patients from orthotopic diversion.

Pelvic lymphadenectomy

Indications

• Bilateral pelvic lymphadenectomy must be performed at the time of any surgery with curative intent★
  • Bilateral pelvic lymphadenectomy should be performed in ALL patients, including those with unilateral bladder wall involvement, due to documented crossover risk to the contralateral lymphatic chain.

Extent of lymphadenectomy

• When performing bilateral pelvic lymphadenectomy, at a minimum, the external and internal iliac and obturator lymph nodes should be removed★
  • To facilitate adequate staging, a standard lymphadenectomy (bilateral external iliac, internal iliac and obturator lymph nodes), at a minimum, needs to be completed with >12 lymph nodes evaluated
  • Submission of separate nodal packets appears to facilitate identification of lymph nodes and is associated with an increased number of reported lymph nodes

SWOG S1011 (NEJM 2024)

• Population: 592 patients with localized muscle-invasive bladder cancer of clinical stage T2 (confined to muscle) to T4a (invading adjacent organs) with two or fewer positive nodes (N0, N1, or N2)
• Randomized to: bilateral standard lymphadenectomy (dissection of lymph nodes on both sides of the pelvis) or extended lymphadenectomy involving removal of common iliac, presciatic, and presacral nodes.
• Primary outcome: disease-free survival
• Results:
  • Median follow-up: 6.1 years
  • Disease-free survival: no significant difference
  • Overall survival: no significant difference
  • Extended lymphadenectomy was associated with higher perioperative morbidity and mortality
• Standard or Extended Lymphadenectomy for Muscle-Invasive Bladder Cancer. Lerner et al. NEJM 2024.

LEA AUO AB 25/02 (European Urology 2019)

• Population: 401 patients with locally resectable T1G3 or muscle-invasive urothelial bladder cancer (T2-T4aM0)
• Randomized to limited (obturator, and internal and external iliac nodes) vs. extended LND (in addition, deep obturator, common iliac, presacral, paracaval, interaortocaval, and para-aortal nodes up to the inferior mesenteric artery).
• Primary outcome: recurrence-free survival
• Secondary outcomes: cancer-specific survival, overall survival, complications
• Results:
  • Median number of dissected nodes: limited 19 vs. extended 31
  • Primary outcome: no significant difference in recurrence-free survival (5-yr RFS 65% extended vs 59%; p=0.36)
  • Secondary outcomes:
    • No significant difference in cancer-specific survival (5-yr CSS 76% vs 65%; p=0.10)
    • No significant difference in overall survival (5-yr OS 59% vs 50%; p=0.12)
    • Clavien grade ≥3 lymphoceles were more frequently reported in the extended LND group within 90 days after surgery.
• Gschwend, Jürgen E., et al. "Extended versus limited lymph node dissection in bladder cancer patients undergoing radical cystectomy: survival results from a prospective, randomized trial." European urology 75.4 (2019): 604-611.

Prognosis

• Despite aggressive surgical therapy, ≈50% of cystectomy patients will ultimately die of disease
• Most recurrences will occur within the 2-3 years after cystectomy
• Prognostic factors following RC
  1. pT stage and presence of nodal metastasis (strongest predictors of recurrence and survival following cystectomy)
  2. Margin status
  3. Presence of lymphovascular invasion
     • In MIBC, presence of LVI is associated with features of aggressive disease and predicts recurrence and survival§
     • Recall, LVI associated with progression in high-risk NMIBC
  4. Presence of hydronephrosis
  5. Molecular markers
  6. Variant histology
  7. Body mass index
  8. Age
  9. Gender
  10. Surgical expertise
  11. Hospital volume
  12. Time from initial diagnosis of muscle invasion to cystectomy (particularly if there is a delay >12 weeks)
• Systemic recurrence rates by stage:
  • pT2: 20-30%
  • pT3: 40%
  • pT4>50%
  • N+: 70%
• The Bladder Cancer Research Consortium and The International Bladder Cancer Consortium have developed nomograms to predict recurrence following radical cystectomy
• Currently, most patients with recurrence after cystectomy are not cured with current systemic therapies

Bladder Preservation/Multimodal Therapy

• A multi-disciplinary team discussion is preferred for patients considering bladder preservation.
• Successful bladder preservation should be viewed as a multimodal therapy involving:
  1. Aggressive TUR
  2. Systemic chemotherapy
  3. Radiation therapy
  • Historical series have demonstrated inferior results with single modality therapy (radical TUR, chemotherapy alone, or radiation alone) compared to that of radical cystectomy.

Patient selection

• Indications★
  1. Patients with newly diagnosed non-metastatic MIBC who desire to retain their bladder
  2. Patients with significant comorbidities for whom radical cystectomy is not a treatment option, clinicians should offer bladder
     • Overall, bladder preserving therapy has been associated with decreased survival compared to RC
       • Patients who are deemed “medically fit” to undergo cystectomy should be offered cystectomy as the standard of care
     • Studies that support bladder preserving strategies, as a general rule, have highly select patient populations
     • Bladder preservation should be undertaken with the goal of curative therapy and to maintain a functionally intact bladder
• Ideal characteristics for bladder preservation (4):★
  1. Unifocal tumor
  2. No CIS
  3. No evidence of hydronephrosis
  4. A tumor that can be completely transurethrally resected
• Contraindications
  • Relative
    1. Large tumors unable to be resected by TURBT
    2. Multifocal CIS
    3. T3/T4 tumors,
    4. Presence of hydronephrosis
    5. Non-urothelial carcinoma
       1. Patients with adenocarcinomas, sarcomas, and squamous cell carcinomas have not been included in prospective studies of radiation-based bladder preservation
  • Unknown how variant histology affects outcomes associated with multi-modal bladder preserving therapy
• In patients under consideration for bladder preserving therapy, maximal debulking transurethral resection of bladder tumor and assessment of multifocal disease/carcinoma in situ should be performed
  • In multiple prospective trials, the ability to resect all tumor predicted the best response to bladder preserving therapies.
  • Random biopsies may help ensure that there is no associated CIS.

Multi-modal/Trimodal bladder preserving therapy

• Most of the literature supporting multi-modal bladder preserving therapy with radical cystectomy is from one RCT and several observational studies that have compared EBRT with and without chemotherapy vs. radical cystectomy[3]
• Includes (3):
  1. Maximal transurethral resection of bladder tumor
  2. Chemotherapy combined with external beam radiation therapy
  3. Ongoing cystoscopy to evaluate response
• Radiation sensitizing chemotherapy
  • Should be included when using multi-modal therapy with curative intent.
    • Radiation with concurrent chemotherapy is superior to radiation alone.
  • Several radiosensitizing chemotherapeutic agents have been shown safe and effective for trimodal bladder cancer therapy
    • Various regimens of neoadjuvant, concurrent and adjuvant cisplatin-based regimens (e.g., cisplatin alone, CMV, cisplatin + paclitaxel or cisplatin + gemcitabine) have been studied.
    • Alternatives for cisplatin-ineligible patients include gemcitabine or 5-fluorouracil and mitomycin C.
    • Carboplatin should not be used as a radiosensitizer unless there are contraindications to cisplatin, 5-FU, and gemcitabine.
      • Carboplatin has been found to be inferior to cisplatin in multimodal bladder preserving therapy
• Patient selection
  • AUA (4):
    1. Unifocal
    2. No CIS
    3. No evidence of hydronephrosis
    4. A tumor that can be completely transurethrally resected
  • CUA (6):
    1. Unifocal
    2. No CIS
    3. No hydronephrosis
    4. Small (<5cm) tumour
    5. Good bladder function
    6. Patient motivated for bladder preservation
• Patients with obvious T3 disease on imaging, multifocal tumors, and/or incomplete macroscopic tumor resection are also suboptimal candidates for bladder preservation
• Strategies for trimodal bladder preservation (2): split- vs. continuous-course therapy
  • Split-course
    • Based on the premise of midtreatment restaging
      • Patients are administered induction chemoradiation therapy to ≈40 Gy, which is followed by restaging with cross-sectional imaging and endoscopic evaluation.
      • If persistent invasive disease [even if lower stage] is noted, RC is recommended. Those without persistent invasive disease undergo consolidative chemoradiotherapy to ≈64 Gy.
  • Continuous-course
    • Involves a full course of chemoradiation therapy followed by an endoscopic restaging examination 6 months after therapy to allow time for an adequate response to therapy.
  • Regardless of approach, maximal tumor debulking before trimodal therapy is critical to optimize therapeutic results
• Follow-up
  • For medically operable patients receiving staged multi-modal therapy, clinicians should offer a mid-course evaluation to allow for the early selection of non-responders before consolidation radiotherapy is given
  • Following completion of bladder preserving therapy, patients should have a follow up cystoscopy with biopsy to identify occult persistent malignancy, and undergo regular surveillance with CT scans, cystoscopy, and urine cytology
    • Those who are biopsy-proven complete responders to bladder preserving protocols remain at risk for both invasive and non-invasive recurrences as well as new tumors in the upper tracts.
    • No direct evidence to determine optimal frequency of surveillance, published protocols recommend:
      • Cystoscopy per high-risk NMIBC schedule
      • Cross-sectional imaging of the abdomen and pelvis and chest imaging every 6 months for the first 2 years
  • Unclear what proportion of patients who, having initially chosen bladder preservation, ultimately require cystectomy in a non-study setting.[4]

Maximal TURBT/partial cystectomy

• See Cystectomy Chapter Notes
• See 2019 CUA MIBC Guideline Notes
• Patients with MIBC who are medically fit and consent to radically cystectomy should not undergo maximal TURBT or partial cystectomy as primary curative therapy
  • Therapies other than radical cystectomy (e.g., partial cystectomy, TURBT alone, chemotherapy alone, or radiation alone) and multi-modal bladder preserving therapy are associated with increased risk of all-cause mortality
• Patients who are unfit for cystectomy and multi-modal bladder preserving therapy may be offered
  • Radical, maximal TURBT alone if they have a tumor that can be macroscopically resected completely, and for which repeat TURBT is negative OR
  • Partial cystectomy, bilateral pelvic lymphadenectomy and perioperative chemotherapy for cisplatin-eligible patients
    • If they meet the following criteria:
      1. Accessible tumor location
      2. Size <3cm
      3. No multi-focal CIS
      4. No hydronephrosis
      5. Adequate bladder function
      6. No residual T1 or higher stage disease
• Patients should be informed that approximately 40% of patients treated in this manner will ultimately require cystectomy and may have an increased risk of bladder cancer mortality.
• For patients with MIBC that have chosen maximal TURBT, no further treatment may be required if they have a tumor that can be macroscopically resected completely, and for which repeat TURBT is negative.**Studies have demonstrated that a significant proportion of patients with small MIBC’s who have a negative re-resection may be locally controlled by TURBT.
• For cisplatin-eligible patients with MIBC patients that have chosen partial cystectomy and pelvic lymphadenectomy, perioperative chemotherapy should be offered.

Primary chemotherapy

• Limited data on chemotherapy alone
  • Population: 63 patients who declined cystectomy after achieving a complete response with neoadjuvant chemotherapy
  • Results:
    • At a minimum of 5 years of follow-up
      • 36% of patients ultimately died of bladder cancer, of which the majority relapsed with invasive disease in the bladder
      • 64% of patients were alive and 54% exhibited an intact bladder.
  • Herr, Harry W. "Outcome of patients who refuse cystectomy after receiving neoadjuvant chemotherapy for muscle-invasive bladder cancer." european urology 54.1 (2008): 126-132.

Primary radiotherapy

• For patients with MIBC, clinicians should not offer radiation therapy alone as a curative treatment

Bladder preserving treatment failure

• Patients who are medically fit and have residual or recurrent muscle-invasive disease following bladder preserving therapy should be offered radical cystectomy with bilateral pelvic lymphadenectomy
  • ≈30% of those selected for treatment by multi-modal bladder preserving therapy will have an invasive recurrence
• In patients who have a non-muscle invasive recurrence after bladder preserving therapy, clinicians may offer either local measures, such as TURBT with intravesical therapy, or radical cystectomy with bilateral pelvic lymphadenectomy.

Urologyschool.com Summary of Treatment of MIBC

• First-line: NAC + RC
• Second-line: RC +/- AC
• Third-line: multi-modal therapy
• Fourth-line: maximal TURBT or partial cystectomy if they meet certain criteria

Follow-up★

• Imaging
  • Chest and cross-sectional imaging of the abdomen and pelvis (CT or MRI): 6-12 month intervals for 2-3 years and then may continue annually
    • The overall prevalence of upper tract urothelial carcinoma after cystectomy ranges from 1-6%
    • Cross sectional imaging is preferably with intravenous contrast and delayed images to evaluate the collecting system and also other sites of disease.
    • Imaging beyond 5 years should be based on shared decision making between the patient and clinician.
• Laboratory values and urine markers
  • Following therapy for MIBC, patients should undergo laboratory assessment of electrolytes, renal function, +/- vitamin B12 at 3-6 month intervals for 2-3 years and then annually thereafter
    • Patients may experience metabolic derangements and declines in renal function over time associated with urinary diversion
    • Vitamin B12 levels should be assessed in patients with resection of > 60 cm of ileum and in those patients in whom the terminal ileum is utilized as there is an increased risk of deficiency and consequent neurological damage
    • Routine frequent CBC and liver function testing for cancer surveillance has not been validated
    • Insufficient data to support the routine use of cytology or urine-based tumor markers in detection of upper tract urothelial cancers
      • Urine collected from intestinal urinary diversion or previously irradiated bladders may contain desquamated intestinal epithelial cells or atypia due to therapy, which may lower the diagnostic specificity.
  • In patients with a retained urethra following radical cystectomy, the urethral remnant should be monitored for recurrence
    • Urethral wash cytology may be a valuable tool in higher risk patients with a retained urethra. This should be considered during follow up, and patients should undergo physical examination of the urethra and discussion of any urethral symptoms such as urethral discharge or spotting.

• Patient survivorship
  • Clinicians should discuss with patients how they are coping with their bladder cancer diagnosis and treatment and should recommend that patients consider participating in a cancer support group or consider receiving individual counseling.
  • Clinicians should encourage bladder cancer patients to adopt healthy lifestyle habits, including smoking cessation, exercise, and a healthy diet, to improve long-term health and quality of life.

References

• Wein AJ, Kavoussi LR, Partin AW, Peters CA (eds): CAMPBELL-WALSH UROLOGY, ed 11. Philadelphia, Elsevier, 2015, chap 94
• Chang, Sam S., et al. "Treatment of non-metastatic muscle-invasive bladder cancer: AUA/ASCO/ASTRO/SUO guideline." The Journal of urology 198.3 (2017): 552-559.
• Kulkarni, Girish S., et al. "Canadian Urological Association guideline: Muscle-invasive bladder cancer." Canadian Urological Association Journal 13.8 (2019): 230.