Editing Muscle-Invasive Bladder Cancer (section)

=== Neoadjuvant/adjuvant chemotherapy===

==== Neoadjuvant ====

===== Advantages =====
# '''Better tolerated before surgery, rather than after surgery when patients may experience a delay in chemotherapy administration because of complications or debilitation'''
# '''Patients who present with micrometastatic disease will receive therapy in a more timely fashion when their burden of disease is potentially low'''
# '''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
# '''Assess each individual’s response to therapy'''

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

* '''NAC does not increase perioperative morbidity or complication rates'''

===== Evidence =====
* '''<span style="color:#ff0000">2 large phase III clinical trials have demonstrated an OS benefit with the use of NAC prior to RC</span>'''
** '''<span style="color:#ff00ff">SWOG 8710</span>'''
*** '''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)'''
*** [https://pubmed.ncbi.nlm.nih.gov/12944571/ 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.
** '''<span style="color:#ff00ff">BA06 30894</span>'''
*** Population: 976 patients with MIBC
*** Randomized to neoadjuvant CMV vs. cystectomy alone
*** [https://pubmed.ncbi.nlm.nih.gov/21502557/ 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 '''<span style="color:#ff0000">neoadjuvant chemotherapy was associated with improved:</span>'''
** '''<span style="color:#ff0000">5-year OS: absolute benefit 5%</span>'''
** '''<span style="color:#ff0000">5-year DFS: absolute benefit 9%</span>'''
** '''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'''
** '''<span style="color:#ff0000">Prior to cystectomy, cisplatin-based NAC should be offered to eligible radical cystectomy patients</span>''', utilizing a multidisciplinary approach

====== CUA ======
*'''<span style="color:#ff0000">2019 CUA Muscle-Invasive Bladder Cancer Guidelines</span>'''
**'''<span style="color:#ff0000">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</span>'''

===== Contraindications =====

* '''<span style="color:#ff0000">If ineligible for cisplatin-based NAC, patients should proceed to definitive locoregional therapy (AUA/CUA)</span>'''**'''Carboplatin-based neoadjuvant chemotherapy should not be used for clinically resectable stage cT2-T4aN0 bladder cancer'''

====== AUA ======

*'''<span style="color:#ff0000">2020 AUA Muscle-Invasive Bladder Cancer Guidelines</span>'''
*#'''<span style="color:#ff0000">eGFR < 60ml/min</span>'''
*# '''<span style="color:#ff0000">Heart failure (NYHA Class > 2)</span>'''
*# '''<span style="color:#ff0000">≥Grade 2 hearing loss</span>''' (grading based on Common Terminology Criteria for Adverse Events version 4.0)
*#'''<span style="color:#ff0000">≥Grade 2 neuropathy</span>'''(grading based on Common Terminology Criteria for Adverse Events version 4.0)
*#'''<span style="color:#ff0000">Reduced performance status (ECOG ≥2 or Karnofsky performance status ≤60-70%)</span>'''

====== CUA ======
*<span style="color:#ff0000">'''2019 CUA Muscle-Invasive Bladder Cancer Guidelines'''</span> '''<span style="color:#0000ff">(HE 2 NICE)</span>'''
** '''<span style="color:#ff0000">Absolute (6):</span>'''
**# '''<span style="color:#ff0000">≥Grade </span><span style="color:#0000ff">2 H</span><span style="color:#ff0000">earing loss</span>''' (grading based on Common Terminology Criteria for Adverse Events version 4.0)
**# '''<span style="color:#0000ff">e</span><span style="color:#ff0000">GFR ≤ 50</span>''' ml/min/1.73m2
**# '''<span style="color:#ff0000">≥Grade </span><span style="color:#0000ff">2 N</span><span style="color:#ff0000">europathy</span>''' (grading based on Common Terminology Criteria for Adverse Events version 4.0)
**# '''<span style="color:#ff0000">Untreated </span><span style="color:#0000ff">I</span><span style="color:#ff0000">nfection</span>'''
**# '''<span style="color:#0000ff">C</span><span style="color:#ff0000">ardiac failure (NYHA Class > </span><span style="color:#0000ff">2)</span>'''
**# '''<span style="color:#0000ff">E</span><span style="color:#ff0000">astern Cooperative Group (ECOG) ≥</span><span style="color:#0000ff">2</span>'''
** '''Relative:'''
**# eGFR 50-60 ml/min/1.73m2
**# 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[https://pubmed.ncbi.nlm.nih.gov/30805684/]

===== <span style="color:#ff0000">Timing of radical cystectomy after NAC</span> =====
*'''<span style="color:#ff0000">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</span>''', 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'''

* '''<span style="color:#ff0000">Adverse events related to cisplatin (4):</span>'''
*# '''<span style="color:#ff0000">Nephrotoxicity</span>'''
*# '''<span style="color:#ff0000">Ototoxicity</span>'''
*# '''<span style="color:#ff0000">Neurotoxicity</span>'''
*# '''<span style="color:#ff0000">Diminished cardiac function</span>'''
** '''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 ======
* '''<span style="color:#ff0000">NAC is primarily derived in the urothelial carcinoma setting</span>'''
** '''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[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3117124/ §]
* '''<span style="color:#ff0000">Lack of robust data supporting NAC in pure non-urothelial histologies</span>'''
** '''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 =====
# '''Allows for immediate local treatment''' with cystectomy and avoids any delay in treatment in patients with chemotherapy-resistant tumors
# '''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.
** [https://pubmed.ncbi.nlm.nih.gov/24018020/ 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'''
** '''<span style="color:#ff0000">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)</span>'''

===== 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