Editing CUA: Muscle-invasive Bladder Cancer (2019) (section)

== Management ==

=== UrologySchool.com 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:'''
**# '''pT3/T4 and/or'''
**# '''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):'''
*# '''Positive urethral margin'''
*# '''Men with:'''
*## '''High grade or invasive urethral disease distal to the prostatic urethra'''
*## '''Suspected prostatic stromal involvement'''
*# '''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. <nowiki>https://www.ncbi.nlm.nih.gov/pubmed/28410011</nowiki>
* '''Ideal characteristics for TMT are as follows (6):'''
*# '''Unifocal'''
*# '''Small (<5cm) tumour'''
*# '''No CIS'''
*# '''No hydronephrosis'''
*# '''Good bladder function'''
*# '''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)
*# '''Dome location'''
*# '''Unifocal'''
*# '''Small tumour <2 cm'''
*# '''Minimal or no CIS'''
*# '''No hydronephrosis'''
*# '''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'''