Non-muscle-invasive bladder cancer is typically treated with transurethral resection of bladder tumors (TURBT) to diagnose, stage, and remove visible tumors, followed by intravesical chemotherapy or immunotherapy to prevent recurrence depending on risk level. Bacillus Calmette-Guerin (BCG) immunotherapy is recommended for high-risk non-muscle-invasive bladder cancer to elicit an immune response against tumor cells. Patients undergo cystoscopy surveillance following treatment to monitor for recurrence.

1. Non–Muscle-Invasive
Bladder Cancer
Dr Rojan Adhikari
FCPS II Urology Resident
SDNTC

3. Epidemiology
• Approximately 70% of bladder tumors are NMIBC at presentation
Campbell- Walsh Urology 12th edition ; Aldousari and Kassouf, 2010;
Ta: 70%
T1: 20%
CIS: 10%

5. TURBT: transurethral resection of bladder
tumor
• First-line to diagnose, stage, and treat visible tumors.
• Goal: to make the correct diagnosis and completely remove all visible lesions.
• EUA done before & after TURBT to asses disease extent & residual tumor.
• Muscle must be seen in TURBT specimen before ruling out invasive disease
• Biopsies of apparently uninvolved urothelium should be obtained to rule out occult Tis.
• Biopsy from the prostatic urethra is necessary in some cases

6. Steps to achieve a successful TURBT
Identifying the factors required to assign
• disease risk (number of tumurs, size, multifocality, characteristics, concern for the
presence of CIS, recurrent vs. primary tumour),
• clinical stage (bimanual examination under anaesthesia, assignment of clinical
tumour stage),
• adequacy of the resection (visually complete resection, visualisation of muscle at
the resection base), and
• presence of complications (assessment for perforation)

7. Surgical strategy of resection
• Piecemeal resection in fractions (separate resection of the exophytic
part of the tumour, the underlying bladder wall and the edges of the
resection area) 1
• En-bloc resection using monopolar or bipolar current, Thulium-YAG
or Holmium-YAG laser. It provides high quality resected specimens
with the presence of detrusor muscle in 96-100% of cases 2
1. Richterstetter, M., et al. The value of extended transurethral resection of bladder tumour (TURBT) in the treatment of bladder cancer. BJU Int, 2012. 110: E76.
2. Kramer, M.W., et al. Current Evidence of Transurethral En-bloc Resection of Nonmuscle Invasive Bladder Cancer. Eur Urol Focus, 2017. 3: 567.

8. Pathologist should comment on:
• Size
• tumour grade
• depth of tumour invasion,
• presence of CIS
• whether the detrusor muscle is present in the specimen.
• specify the presence of LVI or unusual (variant) histology
• If there is uncertainty over the pathology, a further early re- resection
(2-6 wk.) is indicated.

9. Prostatic urethral biopsies
• Patients with T1G3 Bladder Cancer, the incidence of CIS in the prostatic
urethra was 11.7% 1
• Take the biopsy from abnormal areas in the prostatic urethra and from
the precollicular area (between the 5 and 7 o’clock position) using a
resection loop 1, 2
1. Palou, J., et al. Female gender and carcinoma in situ in the prostatic urethra are prognostic factors for recurrence, progression, and disease-specific mortality in T1G3 bladder cancer patients treated with
bacillus Calmette-Guerin. Eur Urol, 2012. 62: 118.
2. Mungan, M.U., et al. Risk factors for mucosal prostatic urethral involvement in superficial transitional cell carcinoma of the bladder. Eur Urol, 2005. 48: 760

10. Take a biopsy of the prostatic urethra in cases
• bladder neck tumour,
• if bladder carcinoma in situ is present or suspected,
• if there is positive cytology without evidence of tumour in the bladder,
• if abnormalities of the prostatic urethra are visible.
• If biopsy is not performed during the initial procedure, it should be
completed at the time of the second resection.
Brant, A., et al. Prognostic implications of prostatic urethral involvement in non-muscle-invasive bladder cancer. World J Urol, 2019. 37: 2683.

11. Second look TURBT?
Indications
• Residual disease after initial TURBT
• When specimen contained no muscle
• High-grade and/or T1 tumor
• Timing and strategy:
• Most recommend 2-6 weeks after initial TUR
• Should include resection of primary tumor site
Cumberbatch, M.G.K., et al. Repeat Transurethral Resection in Non-muscle-invasive Bladder Cancer: A Systematic Review. Eur Urol, 2018

15. PREDICTING DISEASE RECURRENCE AND
PROGRESSION
• EORTC Genito-Urinary Cancer Group has developed a scoring system
and risk tables
• The basis for the scoring system are individual patient data from
2,596 patients diagnosed with TaT1 tumours, who were randomised
into seven EORTC trials
• Patients with CIS alone, undergo a second TURB or receive
maintenance BCG were not included.
Sylvester RJ, et al: Predicting recurrence and progression in individual patients with stage Ta T1 bladder cancer using EORTC risk tables. Eur Urol.2006;

21. INTRAVESICAL THERAPY
Perioperative Intravesical Therapy
• Single-dose intravesical chemotherapy administered within 6 hours of
resection reduces recurrence of low-risk tumors 1, 2
• Mitomycin C (MMC) appears to be the most effective adjuvant intravesical
chemotherapeutic agent perioperatively, epirubicin is used in Europe 1, 3
• Average recurrence rate was 54% in the TUR-alone group versus 38% in
the TUR-plus-MMC group 4
1. Bosscheiter et al., 2018,
2. uque and Loughlin, 2000; Isaka et al., 1992; Oosterlinck et al., 1993; Sekine et al., 1994; Solsona et al., 1999
3. Witjes and Hendricksen, 2008
4. Nilsson S, et al . A systematic overview of chemotherapy effects in urothelial bladder cancer. Acta Oncol. 2001

22. Sylvester et al., 2004: THE JOURNAL OF UROLOGY® 2004 ; A single immediate postoperative instillation of chemotherapy decreases the risk of recurrence in patients with stage
ta t1 bladder cancer: a meta-analysis of published results of randomized clinical trials

24. Mitomycin C
• MMC is an alkylating agent that inhibits DNA synthesis.
• The drug is usually instilled weekly for 6 to 8 weeks at dose ranges
from 20 to 60 mg.
• used for Low grade, Ta or T1 tumours, and recurrent multifocal TCC
• single-​dose Intravesical therapy is equivalent to that seen using
weekly instillations for 6wk, post-​TURBT
Sylvester RJ, et al. (2004). A single immediate postoperative instillation of chemotherapy decreases the risk of recurrence in patients with stage TaT1 bladder cancer: a meta-​analysis. J Urol

25. • most studies shows MMC a viable option for reduction in recurrence
(but not for progression) in light of its lesser side effects 1
• Adverse effect of MMC include Skin rash- palmar desquamation,
Irritative symptoms and chemical cystitis (10%) and rarely, contracted
bladder
Huncharek et al., 2001, Anticancer research Journal ; Impact of intravesical chemotherapy on recurrence rate of recurrent superficial transitional
cell carcinoma of the bladder: results of a meta-analysis

26. Intravesical Immunotherapy: Bacille Calmette-Guérin
• Over 30 years’ successful application of Bacillus Calmette
Guerin (BCG) to the clinical treatment of bladder cancer has
proved it one of the most promising immunotherapies for cancer
1
• Intravesical BCG results in a robust local immune response 2
• directly reacts to the tumor cells, causing apoptosis,
necrocytosis, oxidative stress, 1
1. Jiansong Han et al, 2020 ; Mechanisms of BCG in the treatment of bladder cancer-current understanding and the prospect
2. Shen et al., 2008

27. Mechanism of action
• Initial step is direct binding to fibronectin within the bladder wall leading to direct
stimulation of cell-based immunologic response 1
• Numerous cytokines involved in the initiation or maintenance of inflammatory
processes including TNF-α, GM-CSF, IFN-γ, and IL-1, IL-2, IL-5, IL-6, IL-8, IL-10, IL-12,
and IL-18 have been detected in the urine of patients treated with intravesical BCG.1
• cytokine induction with preferential upregulation of IFN-γ, IL-2, and IL-12 reflects
induction of a T-helper type-1 (Th1) response 2
• This immunologic response activates cell-mediated cytotoxic mechanisms believed to
underlie the efficacy of BCG and other agents in the prevention of recurrence and
progression 2
1. Ludwig et al., 2004
2. Bohle and Brandau, 2003

28. Jiansong Han et al, 2020 ; Biomedicine & Pharmacotherapy Journal
Mechanisms of BCG in the treatment of bladder cancer-current understanding and the prospect
The model of mechanisms of BCG in bladder cancer.
When BCG is exposed to tumor microenviroment, it attaches to the cell surface and be internalized by tumor cells to
active different pathways such as NF-KB. Cytokines will be released by some immune cells like nuetrophils and
macrophages to attend immune cascade or kill the tumor cells directly

29. • BCG powdered vaccine 80mg is reconstituted with 50 mL of saline
• typically started 2 to 4 weeks after resection, allowing time for re-
epithelialization of the bladder after TURBT, thereby minimizing the potential
for intravasation of live bacteria
• A urinalysis is usually performed immediately before instillation
• After instillation, the patient should retain the solution for at least 1 to 2
hours
• Fluid, diuretic, and caffeine restriction before instillation limits dilution of the
agent by urine and facilitates adequate retention of the agent for 2 hours
1. Lamm et al. 2011
2. Herr, 2012
3. Lamm et al., 2000b

30. BCG Prophylaxis to Prevent Recurrence and
Progression
Conclusion:
• In NMIBC several intravesical therapies are associated with a decreased risk
of recurrence and Progression vs transurethral bladder tumor resection
alone

31. Conclusion
In 403 patients with CIS, BCG reduced the risk of progression by 35%
compared with intravesical chemotherapy.

33. Complications of BCG

35. Bacille Calmette-Guérin: Treatment Schedule
• Several studies and AUA guidelines suggest that a 6-week induction course
• Durations of maintenance therapy based on risk stratification of the tumor 2
• Southwest Oncology Group (SWOG) reported the most significant impact of
maintenance therapy. Patients received a 6-week induction course followed by 3
weekly instillations at 3 and 6 months and every 6 months thereafter for 3 years.1
• intermediate-risk disease, a 1-year course of maintenance BCG was administered at
months 3, 6, and 12 and In patients with high-risk disease, the instillations were
continued every 6 months thereafter up to 3 years. 2
1. Chang et al., 2016
2. Oddens et al. 2013

36. Bohle and Bock,et al 2004, Intravesical bacille Calmette-Guérin versus mitomycin C in superficial bladder cancer: formal meta-analysis of
comparative studies on tumor progression

42. O’Donnell et al: Practical applications of intravesical chemotherapy and immunotherapy in high-risk patients with superficial bladder cancer. Urol Clin North Am 32:121–131, 2005

43. Role of “Early” Cystectomy
• Despite local therapy, many cases of high-grade NMIBC will progress to invasion 1
• Patients of CIS in whom BCG unresponsiveness will have a 50% chance of disease
progression and potential for disease-specific mortality. 1
• Early (3-month) failure for T1 tumors after BCG is associated with an 82%
progression rate. 2
• Ten-year survival after cystectomy for non–muscle-invasive cancer can range
from 67% to 92%. 3
1. Catalona et al., 1987
2. Herr et al., 2000a
3. Lee et al., 2007; Schrier et al., 2004

44. Cystectomy / Radical cystectomy consider in
NMIBC
• high grade tumour
• invading deeply into lamina propria,
• lymphovascular invasion,
• diffuse CIS,
• Tumour in diverticula,
• Tumour involve the distal ureters or prostatic urethra,
• Refractory to initial therapy,
• Tumour too large or anatomically inaccessible to be removed in their
entirety endoscopically.

45. Follow up
• TaT1 tumurs and carcinoma in situ (CIS) on regular cystoscopy.
• Patients with low-risk Ta tumours should undergo cystoscopy at three months.
If negative, subsequent cystoscopy is advised nine months later, and then
yearly for five years. 1
• Patients with high-risk tumours should undergo cystoscopy and urinary
cytology at three months. If negative, subsequent cystoscopy and cytology
should be repeated every three months for a period of two years, and every six
months thereafter until five years, and then yearly. 2
Palou, J., et al. 2009
Soukup, V., et al. 2012
Holmang, S., et al. 2012

46. • Patients with intermediate-risk Ta tumours should have an in-
between (individualised) follow-up scheme using cystoscopy. 1, 2
• Regular (yearly) upper tract imaging (computed tomography-
intravenous urography [CT-IVU] ) is recommended for high-risk
tumours. 1
• Cystoscopy under anaesthesia and bladder biopsies should be
performed when office cystoscopy shows suspicious findings or if
urinary cytology is positive 3
1. Holmang, S., et al. 2012
2. Soukup, V., et al. 2012
3. Niwa, N., et al. 2015

47. • During follow-up in patients with positive cytology and no visible
tumour in the bladder, mapping-biopsies or PDD-guided biopsies and
investigation of extravesical locations (CT urography, prostatic urethra
biopsy) are recommended.
• In patients initially diagnosed with TaLG bladder cancer, use
ultrasound of the bladder during surveillance in case cystoscopy is not
possible or refused by the patient.

48. INDEX PATIENT NO. 1:
• ABNORMAL UROTHELIAL GROWTH BUT NOT PROVEN CANCER
• Standard: Obtain biopsy to confirm grade for all index patients.
• If possible, eradicate all visible tumors.
• If cancer, periodic cystoscopy.
• Option: Single dose of postoperative intravesical chemotherapy

49. INDEX PATIENT NO. 2:
• SMALL-VOLUME, LOW-GRADE Ta
• Recommendation: Single dose of postoperative intravesical
chemotherapy.

50. INDEX PATIENT NO. 3:
• MULTIFOCAL OR LARGE LOW-GRADE Ta, OR RECURRENT LOW-GRADE Ta
• Recommendation: Intravesical BCG or MMC—goal to prevent/ delay
recurrence.
• Option: Maintenance BCG or MMC.

51. INDEX PATIENT NO. 4:
• HIGH-GRADE Ta, T1, OR CIS
• Standard: If T1 disease, but no muscularis in specimen, repeat
resection.
• Recommendation: Intravesical BCG with maintenance therapy.
• Option: Consider cystectomy for select patients.

52. INDEX PATIENT NO. 5:
• HIGH-GRADE Ta, T1, AND/OR CIS AFTER PRIOR INTRAVESICAL
THERAPY
• Standard: T1 disease but no muscularis in specimen, repeat resection.
• Recommendation: Consider cystectomy as therapeutic alternative.
• Option: Further intravesical therapy may be considered.

53. Thank you

55. Bladder biopsies
• biopsies from suspicious urothelium should be taken
• Patients with positive urine cytology, or with a history of HG NMIBC
and in tumors with non-papillary appearance, mapping biopsies from
normal-looking mucosa is recommended 1
• biopsies should be taken from the trigone, bladder dome, right, left,
anterior and posterior bladder wall 1,2
1. Hara, T., et al. Risk of concomitant carcinoma in situ determining biopsy candidates among primary non-muscle-invasive bladder cancer patients: retrospective analysis . Int J Urol, 2009.
2. van der Meijden, A., et al. Significance of bladder biopsies in Ta,T1 bladder tumors: a report from the EORTC Genito-Urinary Tract Cancer Cooperative Group. EORTC-GU Group Superficial Bladder
Committee. Eur Urol, 1999.