Muscle-Invasive Bladder Cancer

See 2020 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
  • 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):***#Elevated alkaline phosphatase
      1. 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

• 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§

Radical Cystectomy

• See Cystectomy Chapter Notes
• 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. Variant histology
    5. Molecular markers
    6. Body mass index
    7. Presence of hydronephrosis
    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

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

• CUA: 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

• CUA (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

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.

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.

Bladder Preservation/Multimodal Therapy

• Patients who are deemed “medically fit” to undergo cystectomy should be offered cystectomy as the standard of care; however, bladder preservation is a reasonable option for those who are highly selected and counseled appropriately. Patients who are medically unfit for surgery or who refuse surgery can be considered for bladder preservation.
• Bladder preservation should be undertaken with the goal of curative therapy and to maintain a functionally intact bladder
• 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.

Trimodal 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

Other treatments

Partial cystectomy

• Partial cystectomy is the treatment of choice for urachal adenocarcinoma
• See 2019 CUA MIBC Guideline Notes

Primary chemotherapy

• RC remains the standard of care in patients who have had a complete response to neoadjuvant therapy; however, patients have refused cystectomy in this setting.
  • 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.

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.