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BLADDER CANCER: MUSCLE-INVASIVE BLADDER CANCER

See 2017 AUA MIBC Guideline Notes and 2019 CUA MIBC Guideline Notes

Presentation

≈75-80% of patients will present with non-muscle invasive bladder cancer (NMIBC) and ≈20-25% will present with MIBC; ≈20% will progress to MIBC after an initial diagnosis of NMIBC
- Patients initially with NMIBC who progress to MIBC have been found to have a worse prognosis than patients initially presenting 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

Management Overview

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 and Pelvic Lymph Node Dissection (PLND) for MIBC

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

Chemotherapy for MIBC

Neoadjuvant
- 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
- Advantages of NAC
  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 of NAC:
  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
- 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
- Cisplatin eligibility is a major determinant of candidacy for NAC
  - Adverse events related to cisplatin:
    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
- CUA Contraindications to NAC 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
- 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 of adjuvant chemotherapy:
  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.
- Disadvantage of adjuvant chemotherapy:
- 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.
NAC vs. Adjuvant
- 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

Immunotherapy for MIBC

Neoadjuvant
- PURE-01 (neoadjuvant pembrolizumab)
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
    - High risk defined as
      - Pathological stage pT3, pT3, 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 pyT4a 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: approximately 20 months
    - Primary outcome: disese-free survival
      - Absolute disease-free survival benefit at 6 months:
        
        All patients: 15% (75% adjuvant nivolumab vs. 60% placebo)
        
        PD-L1 patients: 18% (74% adjuvant nivolumab vs. 56% 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

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

Ideal candidates for bladder preservation in MIBC should have:

CUA (6):
1. Unifocal
2. Small (<5cm) tumour
3. No CIS
4. No hydronephrosis
5. Good bladder function
6. Patient motivated for bladder preservation
Campbell’s (5):
1. Small solitary tumors
2. Limited CIS
3. No hydronephrosis
4. Good bladder function
5. A complete resection of all visible tumors endoscopically
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.

Questions

See 2019 CUA MIBC Guideline Notes

Next Chapter: Unresectable Locally Advanced and Metastatic Bladder Cancer

References

Wein AJ, Kavoussi LR, Partin AW, Peters CA (eds): CAMPBELL-WALSH UROLOGY, ed 11. Philadelphia, Elsevier, 2015, chap 94