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CUA GUIDELINE: MUSCLE-INVASIVE BLADDER CANCER 2019

See AUA Muscle-invasive Bladder Cancer Guidelines 2017

Diagnosis and Evaluation

• Clinical staging (3): TURBT pathology, exam under anesthesia, imaging
• TURBT pathology
• MIBC should be diagnosed with a good quality TURBT including muscularis propria that confirms muscle invasion
• In those rare instances where evidence (radiographic or clinical (e.g. bimanual examination)) supports a clear-cut clinical diagnosis of MIBC and where (i) tumour size precludes safely performing a complete TURBT and/or (ii) complete TURBT is simply not feasible, tumour tissue should still be procured to establish a bladder cancer diagnosis and determine final histology
• Pathologic reporting of TURBT should include data on (5):
• T stage (depth of invasion)
• Histological type (i.e. urothelial, squamous cell, small cell carcinoma, etc), subtypes if there is mixed histology, and any divergent differentiation of urothelial carcinoma (e.g. urothelial carcinoma with squamous, glandular or sarcomatoid differentiation), including variant histology (i.e. micropapillary, plasmacytoid, nested variant, etc.) and an estimate of the proportion of variant histology
• Pure non-urothelial histology (squamous, small cell) are more aggressive
• Variant urothelial histology or extensive glandular/squamous differentiation is associated with more aggressive disease
• Pathology review by a second pathologist, preferably a dedicated GU pathologist, is recommended for all cases of variant histology
• Grade
• Concomitant carcinoma-in-situ (CIS)
• Concomitant CIS has been linked to higher rates of recurrence after RC and worse cancer-specific survival in patients with ≤pT2 disease at RC
• CIS is associated with resistance to radiation
• Lymphovascular invasion (LVI)
• LVI associated with more aggressive disease
• Streeper NM, Simons CM, Konety BR, et al. The significance of lymphovascular invasion in transurethral resection of bladder tumour and cystectomy specimens on the survival of patients with urothelial bladder cancer. BJU Int 2009; 103:475-9.
• Culp SH, Dickstein RJ, Grossman HB, et al. Refining patient selection for neoadjuvant chemotherapy before radical cystectomy. J Urol 2014; 191:40-7.
• Examination under anesthesia
• See Chapter 95
• Should be performed immediately after TURBT to accurately determine clinical stage and resectability(LE 3, moderate recommendation).
• Imaging
• CT chest, abdomen and pelvis is the ideal treatment modality to stage localized MIBC and metastatic bladder cancer
• MRI is an alternative
• Chest imaging (CT or x-ray) should also be performed to rule out metastatic disease or concomitant lung cancer given the preponderance of smoking in urothelial carcinoma patients
• Bone scans are not considered mandatory but should be obtained in the setting of an elevated ALP, hypercalcemia or bony pain
• Currently, the role for PET CT in the staging of bladder cancer remains undefined

Treatment

• Summary
• Multidisciplinary approach
• First-line: NAC followed by RC + PLND
• Second-line: RC +/- AC, if appropriate
• Third-line: TMT
• Fourth-line: radiation + chemotherapy

 

• Chemotherapy
• Neoadjuvant chemotherapy (NAC)
• All eligible patients with cT2-T4a N0 M0 urothelial carcinoma of the bladder should be encouraged to receive cisplatin-based combination chemotherapy as NAC prior to radical local therapy
• Note that Grossman/SWOG trial was of patients with cT2-T4a N0 M0 urothelial carcinoma of the bladder
• The role of NAC in pure non-urothelial carcinoma (squamous cell carcinoma, adenocarcinoma, etc.) is not defined and should not be utilized
• Campbell’s: Exception, NAC is standard for pure neuroendocrine and small cell bladder carcinoma
• NAC Regimen Options (3):
• Gemcitabine/Cisplatin (GC)
• MVAC
• dd-MVAC
• Contraindications to cisplatin-based NAC
• Absolute (6, first 4 same as AUA):HE 2 NICE
• ≥Grade 2 Hearing loss (grading based on Common Terminology Criteria for Adverse Events version 4.0)
• eGFR ≤ 50 ml/min/1.73m2
• To optimize renal function in patients considering and/or eligible for NAC, malignant ureteric obstruction should be relieved via percutaneous drainage nephrostomy tubes
• ≥Grade 2 Neuropathy (grading based on Common Terminology Criteria for Adverse Events version 4.0)
• Untreated Infection
• Cardiac failure (NYHA Class > 2)
• Eastern Cooperative Group (ECOG)≥2
• Relative (2):
• eGFR between 50-60 ml/min/1.73m2
• History of recurrent infection and concomitant immunosuppression
• Patients with contraindications to cisplatin-based NAC should proceed directly to radical local therapy i.e. there is no second-line regimen for NAC
• After 2/4 cycles of GC or conventional MVAC NAC, restaging should be performed to ensure treatment response or stable disease during chemotherapy.
• In the event of non-metastatic progressive disease or significant toxicity to chemotherapy that precludes its delivery, NAC should be discontinued and cystectomy performed within 4-6 weeks of last chemotherapy.
• Patients receiving ddMVAC, given every 2 weeks, do not need restaging in the midst of chemotherapy as the short course of treatment precludes the need for imaging
• Adjuvant chemotherapy
• In patients who do not receive NAC prior to cystectomy, adjuvant cisplatin-based combination chemotherapy (GC, MVAC or dd-MVAC) should be offered to those eligible patients with:
  1. pT3/T4 and/or
  2. N+ disease
• Unresectable disease
• See 2019 CUA Consensus Statement on locally advanced and metastatic urothelial carcinoma
• Patients with non-metastatic, clinically unresectable, cT4b or cN+ tumours should be offered induction (primary) cisplatin-based combination chemotherapy with either GC, MVAC or ddMVAC if eligible, or an alternative combination chemotherapy regimen if platinum-ineligible (e.g. Gemcitabine/Carboplatin), single-agent chemotherapy or enrolment in a clinical trial, if available

 

• Radical cystectomy
• The standard therapy for localized MIBC is radical cystectomy
• Timing of cystectomy
• Cystectomy should be done 4-6 weeks (at most 10 weeks) after completion of NAC to avoid compromising survival
• The optimal timing of radical cystectomy where NAC has not been administered is within 6 weeks of TURBT
• Patients scheduled for radical cystectomy are recommended to receive perioperative optimization according to endorsed Enhanced Recovery after Abdominal Surgery (ERAS) protocols.
• Orthotopic urinary diversion should be offered to all eligible patients as an alternative to an ileal conduit.
• An intraoperative frozen section evaluation of the urethral margin should be performed prior to creating an orthotopic diversion.
• Urethrectomy should be performed in/contraindications to orthotopic neobladder (4):
1. Positive urethral margin
2. Men with:
   1. High grade or invasive urethral disease distal to the prostatic urethra
   2. Suspected prostatic stromal involvement
3. Women with bladder neck tumours
• Cystectomy pathology
• The final pathology report should contain information on: histology (including variants), stage, grade, presence of concomitant CIS, presence of LVI, number of lymph nodes, number of positive lymph nodes, and surgical margin status
• Assessment of accompanying reproductive organs (prostate, uterus, cervix, ovaries, vagina) should be performed to rule out occult secondary malignancy and for determination of final pathologic stage

• Trimodal therapy (TMT)
• Involves radical TURBT + external beam radiotherapy + concomitant systemic chemotherapy
• With TMT, maximal/radical TURBT should be performed to clear all visible tumour prior to initiation of chemoradiation
• Different chemotherapy regimens have been used, but most evidence exists for cisplatin and mitomycin C plus 5-FU
• Can be offered to select patients wishing to preserve their bladder, those unfit for cystectomy or those refusing cystectomy
• In carefully selected patients, TMT offered in a multidisciplinary bladder cancer clinic yielded moderate-term disease-specific survival rates rivalling that of RC (73% for RC, 77% for TMT).
• Kulkarni, Girish S., et al. "Propensity score analysis of radical cystectomy versus bladder-sparing trimodal therapy in the setting of a multidisciplinary bladder cancer clinic." Journal of Clinical Oncology 35.20 (2017): 2299-2305. https://www.ncbi.nlm.nih.gov/pubmed/28410011
• Ideal characteristics for TMT are as follows (6):
  1. Unifocal
  2. Small (<5cm) tumour
  3. No CIS
  4. No hydronephrosis
  5. Good bladder function
  6. Patient motivated for bladder preservation
• Only ≈20-25% of surgically fit patients meet the criteria for TMT bladder preservation
• [Random bladder biopsies (plus prostatic urethral biopsy) should be performed prior to TMT to rule out occult disease; not explicitly stated in guidelines but similar concept to rule out occult CIS as with partial cystectomy?]

 

• Radiotherapy
• Should be offered in combination with chemotherapy (either cisplatin or 5-FU/MMC or Gemcitabine)
• A smaller randomized NRG/RTOG trial demonstrated similar 3-year distant metastases-free survival regardless if the chemotherapeutic regimen utilized was 5-FU-based or gemcitabine-based.
• As monotherapy, only acceptable in patients who are ineligible for both RC and chemotherapy
• Radiotherapy alone has been shown in a large randomized control trial to be inferior to radiotherapy plus chemotherapy.
• Currently no well-defined role for neoadjuvant or adjuvant radiotherapy for localized MIBC

• Partial cystectomy
• Partial cystectomy for MIBC is discouraged and should only be considered in specific situations:
• Recall, bottom 5 similar as TMT (except tumour <5cm and no CIS for TMT)
1. Dome location
2. Unifocal
3. Small tumour <2 cm
4. Minimal or no CIS
5. No hydronephrosis
6. Good bladder capacity
• Random bladder biopsies (plus prostatic urethral biopsy) should be performed prior to partial cystectomy to rule out occult disease [i.e. CIS]
• Campbell’s 11th edition, Chapter 94, page 2233: “The presence of CIS is considered by most to be a contraindication to partial cystectomy” [different than CUA Guidelines which allow minimal CIS]
• Pelvic lymph node dissection should be performed at the time of partial cystectomy

Special scenarios

• Oligometastatic disease
• See Campbell’s Yo Notes Chapter 94, section on 2019 CUA Consensus Statement

Follow-up and Quality-of-Life

• Quality of Life (QOL) in the form of a validated Patient Reported Outcome (PRO) measure or QOL instrument should be captured for all patients at each visit.
• A recent study suggested improved survival in patients reporting PROs.
• Cystectomy patients are at risk of long-term sexual dysfunction, urinary complications (recurrent infections, uretero-enteric anastomotic strictures, stones, renal failure) and bowel dysfunction (diarrhea or constipation).
• TMT patients may experience sexual dysfunction, voiding and storage symptoms from urethral strictures or radiation cystitis, or bowel toxicity (radiation enteritis or proctitis).
• Downstream toxicity from perioperative chemotherapy may also occur (e.g. coronary artery disease, peripheral neuropathy, ototoxicity).
• Follow-up schedules should be tailored to final pathologic TNM staging
• Follow-up visits after radical cystectomy should include:
• Imaging:
• Metastasis
• Upper tract to assess for hydronephrosis or recurrence
• Laboratory:
• Detect metabolic complications of diversion
• In patients at high risk for urethral or upper tract recurrence, urethral washings +/- urethroscopy and urine should be collected for cytologic examination at interval follow up visits
• Patients treated with a bladder preservation approach (radiotherapy-based or partial cystectomy) should also receive, in addition to the same investigations performed for radical cystectomy patients, long term cystoscopic evaluation at each follow up visit to survey the remaining urothelium
• Intravesical recurrences after bladder preservation may be managed as per primary bladder tumours based on pathologic assessment after TURBT. Careful consideration for radical cystectomy should occur for high risk recurrences.

Supportive and Palliative Care

• For patients with localized, non-metastatic MIBC who are unfit for radical intervention (RC or TMT), an aggressive endoscopic approach (“radical TURBT”) can be performed to achieve local control
• Palliative care consultation should be requested early on in the care of incurable/unresectable patients
• Palliative cystectomy can be performed in select cases, with non-curative intent, for intractable hematuria or pelvic pain secondary to the bladder tumour
• Palliative radiotherapy may also be offered for intractable hematuria or bony pain secondary to metastatic disease
• Palliative chemotherapy (e.g., gemcitabine) may be offered to patients with unresectable or metastatic disease who are ineligible for or have failed platinum-based combination chemotherapy

 

Questions (includes 2017 AUA MIBC Guidelines content)

1. Based on the control arms of trials evaluating NAC in MIBC, what is the approximate pT0 rate in patients undergoing RC without NAC?
2. What are the recommended chemotherapy regimen options for NAC?
3. BONUS: describe SWOG 8710
4. What are the components of MVAC?
5. What is the mechanism of action of gemcitabine? Cisplatin?
6. What toxicities are associated with cisplatin?
7. What is the OS benefit of NAC?
8. What are the absolute contraindications to NAC? Relative?
9. What is the preferred management of patients with contraindications to NAC?
10. A patient agrees to undergo NAC with GC. When will you see them next in follow-up?
11. When should a patient undergo radical cystectomy after receiving NAC?
12. If a patient does not receive NAC, who should be referred for adjuvant chemotherapy?
13. If a patient does not receive NAC, when should the cystectomy be done in relation to timing of the TURBT?
14. What are the indications for a urethrectomy as per the CUA MIBC guidelines?
15. As per the CUA MIBC guidelines, what patients are ideal for TMT?
16. What are the ideal characteristics to consider partial cystectomy in MIBC?
17. As per the AUA MIBC guidelines, what are the absolute contraindications to a continent diversion?
18. What are the most common sites of metastasis?
19. As per the AUA MIBC guidelines, which laboratory investigations should be ordered during the follow-up of a patient treated for MIBC?

 

Answers

1. Based on the control arms of trials evaluating NAC in MIBC, what is the approximate pT0 rate in patients undergoing RC without NAC?
   • 15%
2. What are the recommended chemotherapy regimen options for NAC?
   • 3 recommended chemotherapy options for NAC in MIBC:
1. Gemcitabine-cisplatin
2. MVAC
3. ddMVAC (dose-dense MVAC)
3. BONUS: describe SWOG 8710
   • SWOG 8710 randomized approximately 300 patients to MVAC vs. RC alone and found a 14% benefit in OS at 5-years, but did not reach statistical significance (p=0.06)
4. What are the components of MVAC?
   • Methotrexate, vinblastine, Adriamycin, cisplatin
5. What is the mechanism of action of gemcitabine? Cisplatin?
   • Gemcitabine: pyrimidine antagonist
   • Cisplatin: alkylating agent
6. What toxicities are associated with cisplatin?
   • The main 4 toxicities (related to contraindications) associated with cisplatin and include:
1. Nephrotoxicity
2. Ototoxiciy
3. Neurotoxicity
4. Diminished cardiac
7. What is the OS benefit of NAC?
   • 5% at 5 years
8. What are the absolute contraindications to NAC? Relative?
   • 6 absolute contraindications to NAC in MIBC:
1. eGFR < 50
2. Heart failure (NYHA III or IV)
3. ≥grade 2 neuropathy
4. ≥grade 2 hearing impairment
5. Untreated infection
6. ECOG ≥2
• 2 relative contraindications to NAC in MIBC:
1. eGFR 50-60
2. history of recurrent infection or concomitant immunosuppresion
9. What is the preferred management of patients with contraindications to NAC?
   • Radical local therapy, carboplatin-based neoadjuvant chemotherapy should not be prescribe for clinically resectable stage cT2-T4aN0 bladder cancer
10. A patient agrees to undergo NAC with GC. When will you see them next in follow-up?
    • After 2 of the 4 cycles with a CT scan to evaluate response to treatment
11. When should a patient undergo radical cystectomy after receiving NAC?
    • CUA says within 4-6 weeks and before 10 weeks after completing NAC
    • AUA says within 6-8 weeks and before 4 months of completing NAC
12. If a patient does not receive NAC, who should be referred for adjuvant chemotherapy?
    • pT3+ or N+ disease
13. If a patient does not receive NAC, when should the cystectomy be done in relation to timing of the TURBT?
    • Within 6 weeks of TURBT
14. What are the indications for a urethrectomy as per the CUA MIBC guidelines?
    • 4 indications for urethrectomy:
1. Positive urethral margin
2. Men with HG or invasive urothelial carcinoma distal to prostatic urethra
3. Men with suspected prostatic urethral stromal involvement
4. Women with bladder neck tumours
15. As per the CUA MIBC guidelines, what patients are ideal for TMT?
    • Ideal patients for TMT have 5 characteristics:
1. Small (<5cm) tumour
2. No CIS
3. No hydronephrosis
4. Good baseline bladder function
5. Patient motivated for bladder preservation
16. What are the ideal characteristics to consider partial cystectomy in MIBC?
    • There are 6 characteristics considered ideal for partial cystectomy:
1. Solitary tumour
2. Small (<2cm) tumour
3. Dome location
4. No CIS
5. No hydronephrosis
6. Good bladder capacity
17. As per the AUA MIBC guidelines, what are the absolute contraindications to a continent diversion?
    1. Insufficient bowel segment length
    2. Inadequate motor function or psychological issues that limit the ability to perform self-catheterization
    3. Inadequate renal or hepatic function that increases the risk metabolic abnormalities as a consequence of reabsorption of urine from continent diversions (e.g. an eGFR < 45)
    4. Cancer at the urethral margin (specifically for orthotopic neobladder)
    5. Significant urethral stricture disease that is not correctable
18. What are the most common sites of metastasis?
    • Bone, liver, lungs
19. As per the AUA MIBC guidelines, which laboratory investigations should be ordered during the follow-up of a patient treated for MIBC?
    • Electrolytes, Cr, and vitamin B12