Editing Non-Muscle Invasive Bladder Cancer

'''See 2016 AUA/2021 CUA NMBIC Guideline Notes'''

== Diagnosis of NMIBC ==

* '''See Bladder Cancer: Diagnosis & Evaluation'''
* '''≈75-80% of patients will present with NMIBC and ≈20-25% will present with MIBC and/or metastatic disease'''
** '''Of patients with NMIBC, 70% are Ta, 20% are T1, and 10% are CIS'''
*** Majority of Ta tumours are low-grade
*** T1 tumours are almost always high-grade (2% of T1 tumours are classified low-grade)
*** Adjusted incidence of stage Ta has significantly increased, while stages Tis and T1 have slightly decreased

== Prognosis of NMIBC ==

* '''Recurrence rate: ≈60-70%'''
* '''Progression rate to a higher grade or stage: ≈20-30%'''
* '''Risk factors for recurrence and progression in NMIBC''' (2015 CUA NMIBC Guidelines) '''(6): Girish''' (or other name with G) '''Sends Sexy Notes, Chocolates, and Roses'''
*# '''Grade (most important)'''
*#* '''Grade more important than stage''' (unlike other cancers where stage is more important)
*##* '''High-grade tumors progress with similar frequency regardless of whether they are invasive (T1) or non-invasive (Ta)'''
*##* '''Stage Ta are usually LG; however, ≈7% of Ta disease is HG'''
*# '''Stage (second most important)'''
*#* TaLG: high recurrence rate (≈55%), but much lower stage '''progression rate ≈6%'''
*#* T1HG: high recurrence rate (≈45%) and high progression rate ≈17% [different numbers than Chapter 93]
*# '''Size of tumour (>3 cm)'''
*# '''Number of tumours'''
*# '''Recurrence rate prior''' (>1 per year)
*# '''CIS'''
*#* If CIS is treated only with TURBT,
*#** High risk of recurrence (as high as 90%)
*#** High risk (> 50%) for progressing to muscle-invasive disease.
*#* Even patients with a complete response to intravesical BCG will experience progression in 30% to 40% of cases on longitudinal follow-up
*#* Concomitant CIS is associated with significantly increased risk of disease progression and disease-specific mortality
** '''2016 AUA NMIBC Guidelines:''' separated into recurrence vs. progression, same factors as CUA):
*** '''Recurrence: prior recurrence rate, number of tumours, tumour size'''
*** '''Progression: T-stage, grade, presence of CIS'''
** Probability of recurrence and progression of NMIBC can be calculated based on these 6 factors with thee European Organization for Research and Treatment of Cancer (EORTC) risk tables.
*** These tables were developed and based on individual patient data from 2596 patients diagnosed with Ta/T1 tumours who were randomized in 7 EORTC trials.
*** Note that the EORTC risk calculator likely overestimates the risk of recurrence and progression, as very few of the patients in these prospective trials received intravesical BCG
* '''Other risk factors'''
** '''Mentioned in 2021 CUA NMIBC Guidelines (5):'''
**# '''Age > 70 yr'''
**# '''Extensive invasion of the lamina propria'''
**#* Extent of invasion of T1 tumours has been evaluated using two different criteria:
**### Micrometric: evaluates the millimetric extent of invasion into the lamina propria
**### Microanatomic: evaluates the level of invasion in relation to the muscularis mucosa (T1a – no muscularis mucosa invasion, T1b – invasion at the level of the muscularis mucosa and T1c – invasion beyond the muscularis mucosa)
**##* No single approach has been universally adopted
**# '''Lymphovascular invasion (LVI)'''
**#* '''Retrospective studies demonstrate that the presence of LVI is an independent factor for progression in patients with high-risk NMIBC'''.
**#** '''Use of LVI as a prognostic variable on transurethral resection (TUR) specimen requires prospective validation'''
**#* In NIMBC, LVI is associated with increased risk of recurrence and progression in BCG-treated patients with T1 NMIBC§
**# '''Aggressive histological variancts such as (3): micropapillary, plasmacytoid, and sarcomatoid'''
**#* See Bladder Cancer: Pathology & TNM Staging
**#* '''Associated with under-staging and early progression to muscle invasive disease'''
**# '''First assessment after TURBT'''
**#* Persistent disease at the first surveillance cystoscopy after induction intravesical treatment has been shown to be a risk factor associated with progression
** '''Mentioned in Campbell’s'''
*** '''Tumour architecture: papillary vs. sessile'''
*** '''Status of the remaining urothelium'''

===== '''Genetics of NMIBC''' =====

* '''Tumor suppressor genes are mainly activated by''' allelic deletion of one allele followed by '''point mutations''' of the remaining allele
* '''Microsatellite analysis amplifies DNA repeats in the genome'''
* '''Primary tumour genetic abnormalities in'''
** '''Low-malignant potential NMIBC: chromosome 9, FGFR-3'''
** '''High-malignant potential NMIBC: deletion of RB and TP53'''
* '''Alterations of tumour proten 53 (p53), RB, and PTEN are associated with CIS''' and also carry a very poor prognosis
** '''p53'''
*** '''Most common mutation found in invasive (T2 or higher) bladder tumors'''
*** High-risk p53 lesions have a 75% progression rate, compared with 25% in p53-negative lesions
*** The role of p53 for the prediction of tumor behavior requires prospective validation

===== '''Intravesical therapy''' =====

* '''Either chemotherapy or immunotherapy'''
* '''Either therapeutic''' (treatment of CIS or residual non-visible tumour), '''prophylactic''' (prevention of recurrence and progression of disease'''), or adjuvant in the immediate postoperative setting'''
* '''Intravesical chemotherapy'''
** '''Immediate instillation following TURBT'''
*** '''Commonly used intravesical agents for single post-operative intravesical instillation of chemotherapy include (5):'''
***# '''Gemcitabine''' (SWOG S0337§)
***# '''Mitomycin C (MMC)'''
***# '''Doxorubicin'''
***# '''Epirubicin'''
***# '''Pirarubicin'''
**** '''All equal efficacy as per CUA Guidelines'''
***** As per 11th Ed. Campbell’s, MMC appears to be the most effective adjuvant intravesical chemotherapeutic agent perioperatively, although epirubicin is used in Europe and direct comparative studies are lacking).
**** '''Thiotepa has also been evaluated'''
*** '''Reduces risk of tumour recurrence (absolute risk reduction ≈12%); no benefit of chemotherapy on progression'''
**** '''BCG is the only agent shown to delay or reduce high-grade tumor progression.''' No chemotherapy trials have achieved a significant reduction in progression
**** '''Meta-analysis evaluating intravesical chemotherapy on risk of recurrence'''
***** 13 studies including 2548 patients
***** '''Intravesical chemotherapy''' prolonged recurrence-free interval by 38% (HR: 0.62; 95% confidence interval [CI], 0.50-0.77; p<0.001; I(2): 69%), '''and early recurrences were 12% less likely in the intervention population (ARR: 0.12'''; 95% CI, -0.18 to -0.06; p<0.001, I(2): 0%). '''The number needed to treat to prevent one early recurrences was 8''' (95% CI, 6-17 patients).
***** High risk of bias present in 12 of 13 publications. Quality of evidence for recurrence-free interval was very low and low for early recurrences.
***** Immediate post-transurethral resection of bladder tumor intravesical chemotherapy prevents non-muscle-invasive bladder cancer recurrences: an updated meta-analysis on 2548 patients and quality-of-evidence review. Perlis et. al. Eur Urol. 2013 Sep;64(3):421-30.
*** '''Mechanism of action'''
***** ''':'''
****** '''The two primary theories for recurrent tumor formation:'''
******* '''Genetic field defect exists with multiple new tumors spontaneously arising within the bladder'''
******* '''Local reimplantation of tumor cells after tumor resection'''
******** '''Tumor cell implantation immediately after resection may be responsible for many early recurrences, and this has been used to explain the observation that initial tumors are most commonly found on the floor and lower sidewalls of the bladder, whereas recurrences are often located near the dome as a result of “flotation”'''
******** '''Immediate instillation of intravesical chemotherapy may reducing tumor cell implantation'''
****** '''Intravesical chemotherapy may also have an ablative effect on small occult tumours'''
***** '''Particularly effective for the initial presentation of a (3):'''
*****# '''Solitary'''
*****# '''Low-grade'''
*****# '''Papillary tumor'''
****** '''The incremental benefit in patients with recurrent or multiple tumors is limited.'''
****** '''No benefit has been found in patients with high-grade disease.'''
****** '''Given the number needed to treat of 8, some authors have suggested that intravesical chemotherapy reduces overall cost of care by reducing the need for secondary resections. However, subsequent studies have shown that the tumors prevented are primarily smaller tumors that are often treated in the office or ambulatory surgery setting so the economic impact regarding recurrences remains controversial if recurrences are treated in any manner other than inpatient care'''
***** '''Indications'''
****** '''See 2016 AUA/2021 CUA NMBIC Guideline Notes'''
***** '''Contraindications'''
*****# '''After extensive resection'''
*****# '''Bladder perforation is suspected'''
*****# '''Significant bleeding'''
******* '''Saline irrigation might be a consideration for patients with low- and intermediate risk NMIBC post-TURBT when intravesical chemotherapy is contraindicated (e.g., extensive bladder resection) or unavailable (2021 CUA NMIBC Guidelines)'''
***** '''Steps for Successful Perioperative Administration of Intravesical Chemotherapy'''
*****# '''Include intent to administer perioperative chemotherapy (and agent) on actual operative schedule.'''
*****# '''Contact pharmacy before surgery to have medication available. A written prescription may be required.'''
*****# '''After resection, confirm absence of clinical perforation. Place three-way catheter into bladder while patient is still in operating room. Attach inflow port to saline infusion bag and clamp inflow.'''
*****# '''Administer chemotherapeutic agent through catheter outflow port in recovery room within 6 hours of operation, and clamp outflow tubing with hemostat to allow retention.'''
*****#* '''Efficacy of post-operative instillation significantly decreases if given beyond 24h'''
*****# '''Give order for outflow tubing to be opened 1 hour after administration and for irrigation, to be opened to gravity drainage for next 30-60 minutes.'''
*****# '''Remove Foley catheter and discard in biohazard container.'''
*****# '''Wear gloves'''
***** '''Methods to optimize MMC administration (may reduce recurrence rate further) (4):'''
******# '''Higher concentration (40mg in 20mL of sterile tumour)'''
******# '''Urinary alkalinisation by using sodium bicarbonate to reduce drug degradation'''
******# '''Pre-treatment dehydration'''
******# '''Complete bladder drainage prior to intravesical therapy'''
***** '''Adverse events§'''
****** '''MMC'''
******* '''Local irritative symptoms (most common complication)/chemical cystitis'''
******* '''Rash/Contact dermatitis (second most common complication)'''
******* '''UTI'''
******* '''Hematuria'''
******* '''Fever/chills'''
******* '''Cutaneous hand/foot desquamation'''
******* '''Decreased bladder capacity as a result of contractures'''
******* '''Calcified eschars'''
******* '''Added difficulty of subsequent cystectomy'''
******* '''Serious sequelae and rare deaths have occurred, especially in patients with perforation during resection. Chemotherapy should be withheld in patients with extensive resection or when there is concern about perforation.'''
****** '''Thiotepa'''
******* '''Local irritative symptoms'''
******* '''Myelosuppresion'''
******** '''The low molecular weight of thiotepa predisposes to systemic absorption and myelosuppression'''
**** '''Induction and maintenance chemothera'''