NIMBC ppt final.pptx nonmuscle invasive bladder carcinoma

nonmuscle invasive bladder carcinoma,transitional cell carcinoma[ TCC ], squamous cell carcinoma [ SCC ] , adenocarcinoma

1. Management of Non- Muscle Invasive Urinary bladder

2. Epidemiology Bladder cancer is the 10th most common form of cancer worldwide, with an estimated 549,000 new cases and 200,000 deaths (Table 1). Bladder cancer is more common in men than in women, with respective incidence and mortality rates of 9.6 and 3.2 per 100,000 in men: about 4 times those of women globally . Thus the disease ranks higher among men, in whom it is the sixth most common cancer and ninth leading cause of cancer death National Cancer Institute, Bladder cancer

3. Incidence rates in both sexes are highest in Southern Europe (Greece, with the highest incidence rate in men globally; Spain; Italy), Western Europe (Belgium and the Netherlands), and Northern America, although the highest rates are estimated in Lebanon among women .

4. Other than certain occupational exposures to chemical and water contaminants, cigarette smoking is the main risk factor for bladder cancer and, with the rising prevalence of smoking among women, the attributable risk, at least in the United States, has reached that among men, with 50% of bladder cancer cases attributable to smoking in both sexes

5. Risk Factors

6. Staging

7. Dr chanchal Management of Carcinoma Urinary bladder

8. Superficial Locally Invasive Metastatic Bladder Cancer 70% 25% 5%

9. Bladder Anatomy The urinary bladder has 3 distinct histologic layers Urothelium Lamina Propria Detrusor (Muscularis Propria)

10. CIS Multifocal and can occur in the upper urinary tract 54% - progress to muscle-invasive disease Response to intravesical treatment with BCG or chemotherapy is an important prognostic factor Carcinoma in situ is classified into Primary : isolated CIS with no previous or concurrent exophytic tumours; Secondary : CIS detected during the follow- up of patients with a previous tumour; Concurrent : CIS in the presence of exophytic tumours .[worse prognosis]

11. Diagnosis of non muscle invasive Bladder Cancer

12. Clinical Presentation Hematuria: 80% of TCCs Gross- in 85% Microscopic( in all patients) Degree of hematuria is independent of disease grade/stage Often asymptomatic Bladder irritability Most common with CIS Frequency Urgency Dysuria

13. When is Hematuria a symptom of bladder cancer? Gross painless hematuria 20% - will have urological malignancy 12 %- will have bladder cancer Microscopic hematuria 5.4 % - have a urological malignancy 4.1 %- have bladder cancer Many benign conditions associated with hematuria Symptoms help to distinguish Bladder cancer workup indicated if persistently >3-5 RBCs/high- power field on microscopic examination Some feel workup indictaed for any hematuria Tumer AG et al. BMJ.1997;2:29 Carson CC et al. JAMA.1979;241:149 Amling CL. Curr Pronl Cancer.2001;25:219

14. EVALUATION OF HEMATURIA GROSS HEMATURIA CYSTOSCOPY URINE CYTOLOGY UPPER URINARY TRACT IMAGING[CT SCAN] Sr.PSA [ 10% will have prostatic cancer] MICROSCOPIC HEMATURIA[AUA] CYSTOSCOPY UPPER TRACT IMAGING URINE CYTOLOGY REPEAT EVALUATION Every 6 months for high risk patients

15. Cystoscopy Gold standard Complete visualization of urethral and bladder mucosa: allows biopsy/resection of any lesion Invasive Can be performed with minimal discomfort with topical local anaesthesia in the urethra Standard schedule (q3- 4mo) not based on clinical validation Expensive Sensitivity: 73%, specificity: 68.5% Can be enhanced to 97% sensitivity with 5-aminolevulinic acid – indiuced fluorescence, but not widely practiced Kriegmair M et al. J Urol.1996;155:105

16. Endoscopic Assessment At initial diagnostic cystoscopy it is necessary to document the foll: Tumor – Size, Number, Position Growth pattern ( Papillary or Solid) Mucosa – Normal, red areas or area of red, irregular mucosa Lower tract – The Urethra, The Prostate Bimanual - Is there mass before resection ? exam Is there mass after resection ? Size of mass and mobility

17. Examples of Cystoscopic Imaging

18. Carcinoma in Situ

19. FLUORESCENT CYSTOSCOPY 5- aminolevulinic acid (5- ALA) A precursor to heme biosynthesis is instilled into the bladder Taken up by neoplasms Blue light excites the agent and can detect otherwise unseen CIS on white light Additional detection rate 20% - for all tumors 23% - for CIS 9% - Reduction in risk of recurrence at 9 months Many false + due to inflammatory lesions

20. Fluorescent Cystoscopy

21. Fluorescent Cystoscopy

22. Urine Cytology Standard, non-invasive, tumor- specific marker test Adjunct to cystoscopy Major role Detect high- grade tumors Detect carcinoma in situ Defined criteria for malignant cells Increased nuclear to cytoplasmic ratio Prominent nucleoli Requires trained cytopathologist Significant interpretation variability

23. Urine Cytology… Sensitivity: 38- 60% Misses low grade tumors Specificity: 95- 100% Excellent for high- grade tumors Bladder wash vs voided urine Increase exfoliated cells Invasive Instrument artifact Not cost- effective No significant difference Raitanen MP et al. Eur Urol.2002;41(3):284- 289 Amling CL. Curr Pronl Cancer.2001;25:219 Ramakumar S et al. J Urol.1999;161:388- 394

24. Markers It is generally accepted that none of the currently available tests can replace cystoscopy. However, urinary cytology or biomarkers can be used as an adjunct to cystoscopy to detect invisible tumours, particularly CIS

25. IMAGING INTRAVENOUS UROGRAPHY detect filling defects in the calyces, renal pelvis and ureters, and hydronephrosis CT SCAN in muscle- invasive tumours of the bladder in upper tract tumours tumors located in trigone USG characterisation of renal masses, detection of hydronephrosis and visualisation of intraluminal masses in the bladder

26. Imaging- CT vs. MRI ⚫ CT is unreliable for staging tumours confined to the bladder wall CT is accurate for staging advanced disease MR imaging is superior to CT for staging early tumours Contrast- enhanced MR is probably superior to unenhanced MR for staging bladder cancer CT and MR both have important limitations leading to over staging and under staging. CT and MR are equal in their ability to detect lymph node involvement CT and MR may be useful for monitoring response CT and MR are valuable for detection of recurrence

27. Treatment of Superficial Bladder Cancer

28. Treatment options Transurethral resection (TUR) Laser treatment Photodynamic therapy Intravesical therapy Chemotherapy BCG Interferon BCG + interferon Role of cystectomy

29. TURBT TURBT under regional or general anaesthesia is the initial treatment for visible lesions and is performed to remove all visible tumours and provide specimens for pathologic examination to accurately determine stage and grade.

30. Before TURBT Urine cytology Bimanual Examination Pan cystoscopy- lesion evaluation Avoid over distension- (50-70%)- prevent perforation and improve visibility of CIS

31. Bimanual Examination Under GA , before painting and draping Should be done before and after resection. Fixation or persistence of a palpable mass after resection suggests locally advanced disease. Not necessary if the tumor is clearly small and noninvasive, and is repeated

32. Anaesthesia The use of general anesthesia with muscle- paralyzing agents also prevents obturator reflex. A direct injection of 20 to 30 mL of local anesthetic (lidocaine) into the obturator nerve and its canal can also help.

33. Surgical principles Fexible cystoscope or preferably the 70- degree rigid rod lens, which allows maintenance of the anatomic relationships . low- grade tumours can often be removed without the use of electrical energy . Lifting the tumour edge away from detrusor lessens the chance of perforation After all visible tumour has been resected, an additional pass of the cutting loop or a cold- cup biopsy can be obtained to send to pathology separately to determine the presence of muscle invasion of the tumour base

34. Cauterization Monopolar electrode can transmit and disperse energy through normal saline so sterile water or gylcine should be used. Introduction of bipolar electroresection is reported to allow TUR in saline and to minimize the risk of the obturator reflex, which can predispose to bladder perforation A successful cauterization method involves placing the electrode inside the biopsy site with the bladder under minimal distention.

35. Cauterization When the electrode touches the cut surface of the biopsy crater, the electrical energy will cause the mucosa to contract around the electrode unless the bladder is full. Light irrigation clears the area of blood and vaporization bubbles created during fulguration. Visualizing a small (1 to 2 mm) ring of white coagulation confrms hemostasis and yields less damage to the bladder than that occurring when the biopsy area is “painted” with cautery.

36. Diverticular tumours Signifcant risk of bladder wall perforation, and accurate staging is diffcult to achieve because the underlying detrusor is absent. Low- grade diverticular tumors are best treated with a combination of resection and fulguration of the base. Conservative resection can be followed with subsequent repeat resection if the final pathologic interpretation is high grade. High- grade tumors require adequate sampling of the tumor base, often including perivesical fat, despite the near certainty of bladder perforation. Partial or radical cystectomy should be strongly considered for high-grade diverticular lesions.

37. Anterior wall tumours and tumours at the dome These tumours in patients with large bladders can be difficult to reach. Minimal bladder filling combined with manual compression of the lower abdominal wall to bring the tumor toward the resectoscope facilitates removal. However, modern resectoscopes are long enough to reach the entirety of most bladders. Creation of a temporary perineal urethrostomy offers deeper access but is rarely necessary except in the obese patient with an inaccessible tumor. Digital manipulation through the rectum or vagina can occasionally facilitate resection

38. URETERAL ORIFICES Care must be taken during resection near the ureteral orifIce to prevent obstruction from scarring after fulguration. Pure cutting current causes minimal scarring and may be safely performed, including resection of the orifce if necessary. Resection of the intramural ureter can sometimes lead to complete eradication of the tumor but risks reflux of malignant cells. The clinical implications of this are unclear

39. Pathologist should comment on: Size Tumour grade Depth of tumour invasion, Presence of CIS Whether the 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 reresection should be done within 6 wk.

40. Endoscopic Management Complications Obturator reflex perforation Bleeding TUR Syndrome UO Obstruction Unrecognized disease Perforation Extraperitoneal Intraperitoneal

41. ROLE OF ‘R’ BIOPSIES RANDOM BIOPSY FROM BLADDER Positive urinary cytology and absence of visible tumour in the bladder. Exophytic tumour has a non- papillary appearance. bladder Trigone, bladder dome and from right, left, anterior and posterior walls. PROSTATIC URETHRAL BIOPSY- 11% synchronous malignancy Tumour is located on the trigone or bladder neck In the presence of bladder CIS Multiple tumour Abnormalities of prostatic urethra are visible Biopsy is taken from abnormal areas and from the precollicular area (between 5 and 7o’clock position) using a resection loop.

42. 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 within 6 weeks after initial TUR. Should include complete resection of primary tumor site. Evidences for the need of 2nd look TURBT in T1 /HG tumor- 1/2 will have residual disease on 2nd look [EAU 2010] Under stage is more likely if muscle is absence (50% vs 15%) [Herr JU 1999] 1/4 will have upstage [Herr JU1999] 1/3 will have to change management [Herr JU 1999] 20% increase 5yr DFS in pts with complete TURBT [Germen observational study 2003] European Association of Urology Guidelines.

43. CUETO - http://www.aeu.es/Cueto.html. A scoring model for BCG- treated patients that predicts the short- and long- term risks of recurrence and progression has been published by the Club Urológico Español de Tratamiento Oncológico (CUETO) Gender; Age; Prior recurrence status; Number of tumours; T category; Associated CIS; Tumour grade.

44. Principles of Intravesical treatment

45. Why Intravesical ? It permits high local concentrations of a therapeutic agent within the bladder It can potentially destroying viable tumor cells that remain following transurethral resection of all visible bladder tumor (TURBT).

46. Superficial Bladder Cancer Intravesical Therapy Chemotherapy Thiotepa Doxorubicin Epirubicin Mitomycin Ethoglucid Immunotherapy BCG Interferon Interleukin- 2 KLH [Keyhole limpet hemocyanin

47. Perioperative intravesical Mitomycin C The standard dosage of Mitomycin C is 40 mg in 20 cc sterile water. Best time to install is first 6 hrs, can be given within 24 hrs. Overnight dehydration, Ultrasound- confirmed complete bladder emptying, Alkalinization using 1.3 g of sodium bicarbonate the night before, morning of, and 30 minutes prior to treatment . As Mitomycin C is inactivated by acid urine (Au et al. 2001).

48. Contraindications to perioperative MMC Hypersensitivity, Bladder perforation, Hematuria Myelosuppression, Thrombocytopenia .

49. Conclusion- An immediate single instillation of MMC within 24 h after TURBT reduces the recurrence risk and prolongs the time to recurrence compared with a single delayed instillation of MMC 2 wk after TURBT in patients with NMIBC. Patients treated with adjuvant schedules of chemotherapy also benefit from an immediate instillation.

50. Timing of Perioperative Mitomycin C (MMC) 205 patients with frequently recurrent stage Ta or T1 tumors in FinnBladder IV treated with 2 chemoimmunotherapy regimens - Kaasinen E et al. Eur Urol.2002;42:167

51. N=495, Recurrent ,multifocal Ta & T1 all grades- Intermediate & High Risk Group 1 - BCG RIVM 2 * 10 8 CFU weekly for 6 wk, Group 2 - MMC 20 mg weekly for 6 wk, Group 3 - MMC 20 mg weekly for 6 wk followed by monthly instillations for 3 yr

52. Long- term MMC significantly reduced the risk of tumour recurrence without enhanced toxicity compared with both short- term BCG and MMC in patients with intermediate- and high- risk non–muscle- invasive bladder carcinoma

53. Intravesical Chemotherapy After TUR Net Effect on Recurence rate. - Lamm DL et al, J Urol; 1995; 153(5):1444- 50.

54. Benefits of Intravesical Chemo Modest decrease in short term tumour recurrence (up to 2-3 years) Recurrences same as in controls at 5 years or later No reduction in risk of stage progression Does not improve patient survival

55. Bacillus Calmette-Guerin Live attenuated vaccine produced by serial sub culturing of bovine tubercle bacilli in which the bacilli maintain their antigenicity but virulence is nearly lost.

56. Immunotherapy Bacillus Calmette Guerin (BCG)- Developed from live attenuated strain of M. bovis Stains commonly used in US Tice TheraCYS Stains commonly used in India- Danish 1331 Tokyo 172 Mechenism of action - Acts as immune stimulant: stimulates cellular immune response releasing cytokines IL-1,2,6,8,TNF and IFN gamma. Activation of resting NK cells which further kill the malignant cells via perforin.

57. Mechanism of action of BCG Induces massive local immune response 1 st step- direct binding to fibronectin on bladder mucosa Cytokine induction :IFN-g,IL1,IL2,IL5,IL6, IL8, IL10,IL12,IL18 Th 1 response, influx of granulocytes and mononuclear cells . Cell mediated cytotoxic mechanisms which underlie efficacy of BCG. -Bohle and Brandau, J Urol 2003; 170:964-969.

58. Mechanism of Action of Intravesical BCG

59. Why BCG BCG is the most commonly used agent for intravesical therapy. A number of other intravesical agents have been compared with BCG, but most are inferior, and none has consistently proven to be superior .

60. EAU,AUA,CUA Recommendations For all patients with high- risk non- muscle invasive bladder cancer, a course of intravesical BCG following a restaging TURBT is indicated rather than intravesical chemotherapy. Intravesical BCG is also an option for appropriately selected patients with intermediate- risk disease.

61. Immunotherapy Dose and schedule of BCG- Initiated 3-4 weeks after resection. Induction therapy as weekly for 6 cycles f/b maintenance as 3 weekly for a 1-3 year (3yr better for high risk cases). 50 mg of TICE or 80 Mg Denish 1331 in 50cc of 0.9% NS is instilled via catheter. Catheter must be removed immediately. Ask the pt to hold the urine for 2 hr. S/E : Urinary frequency ,dysuria, hematuria. Arthralgia, rash, fever. Pneumonitis, hepatitis, prostatitis, sepsis.

62. Trails for BCG dose and schedule EORTC phase III trial – Dose – 1/3 dose V/S a full dose Duration - 1- year V/S 3- year treatment Four different arms were made as per doses and duration regarding schedules of BCG maintenance therapy . Conclusion- No meaningful differences in toxicity, progression recurrence and survival were observed in low risk patients. However, the recurrence rate was lowest in high- risk patients treated with the full dose therapy for 3 years , supporting current treatment recommendations.

63. Eortc conclusion There were no significant differences in the toxicity profiles between full and reduced doses of BCG. There was no additional benefit to three years of maintenance treatment compared with one year for patients with intermediate- risk disease given full- dose BCG.

64. Trails for BCG dose and schedule SWOG trial- Compared Induction Vs Induction +3 wkly BCG maintenance therapy. 6 cycle of weekly induction therapy. 3 weekly maintenance therapy at 3, 6, 12, 18, 24, 30, 36 months (3 yrs). No difference in overall 5 yr survival. Improvement in: Recurrence free survival (60% vs 41%) Progession free survival(76% vs 70%) But only 16% tolerated full dose 3 yr therapy.

65. Maintenance BCG SWOG TRIAL(1995)

66. Effect of Intravesical BCG on Disease Progression Reduces stage progression rate Reduces progression to muscle invasion Increases progression- free interval Reduces no of patients requiring cystectomy Increases period of bladder preservation Reduces no of deaths from disease Increases disease specific survival

67. Instructions to the patients after BCG therapy

68. Toxicity of BCG Toxicity can be Acute or Late Onset Acute toxicity can be Local or Systemic. Local toxicity - cystitis , frequency , urgency, gross hematuria , suprapubic pain , urge incontinence , passage of shreds in urine , perineal pain , penile pain.

69. Systemic toxicity Flu like symptoms – fever ,malaise ,chills, myalgia, headache , arthralgia ,anorexia, diarrhea, nausea. Polyarthritis Deranged LFT’s Lung infiltrates Non BCG acid fast bacilli infection Severe hypersensitivity reaction with shock Death

70. Late toxicity of BCG Increased bladder irritability Reduced bladder capacity Granulomatous cystitis Bladder contracture Prostatic urethritis Granulomatous prostatitis

71. Cleveland Clinic Guidelines for management of BCG toxicity Grade 1 : Mild to moderate irritative voiding symptoms, Mild hematuria, Fever<38.5C All symptoms for <48 hrs. Management : Symptomatic only. Anticholinergics , Topical anti spasmodics(phenazopyridine) Analgesics and NSAIDS .

72. Grade II toxicity Severe irritative voiding symptoms , Gross hematuria or any symptoms > 48 hrs. A ssessment : Urine C/S, CXR , LFT Management : S ymptomatic Rx + Treat C/S report with appropriate antibiotics. Start INH 300mg with R’cin 600mg PO till symptoms resolve. Cleveland Clinic Guidelines for Mx of BCG toxicity

73. Grade III toxicity S erious complications with persistant high grade fever, Hemodynamic changes, Allergic reactions (joint pains), Solid organ involvement (epididymitis,osteomyelitis, lung ,liver , kidney,prostate involvement) Management : A ll maneuvers for gr.I & II INH 300mg + R’cin600mg for 3-6 mths. Ethambutol 15mg/kg/day if solid organ involvement Prednisone 40 mg/day if response inadequate IV steroids(with antibiotic cover) in septic shock Cleveland Clinic Guidelines for mx of BCG toxicity

74. Contraindications to BCG Absolute contraindications Immunocompromised patients Immediately after TURBT( intravasation and septic death) Gross hematuria(intravasation risk) Traumatic catheterisation Total incontinence(patient will not retain the agent) Past h/o BCG sepsis Relative contraindications UTI (intravasation risk) Liver disease (cannot give INH if sepsis occurs) Personal H/O TB Poor performance status Advanced age( especially >80yrs)

75. Specific scenario On follow up if Cytology +ve with Cystoscopy –ve  Cystoscopy plus- Imaging of urinary tract Mapping biopsies TUR biopsy of prostate Cytology of upper tract Ureteroscopy If biopsy +ve then treat accordingly- Upper tract positive Prostate positive. Prostatic urethra positive. If biopsy –ve close follow up

76. FOUR SUBTYPES OF BCG FAILURE BCG refractory disease -Failure to achieve a disease free state by 6 mon. after initial BCG therapy OR -Either maintenance or re- t/t at 3 mon. due to either persistent or rapidly recurrent disease -Also include any progression in stage or grade or disease extent by 3 mon after the 1 st cycle of BCG (non- improving or worsening the dis) BCG resistant disease - Persistence of disease at 3 mon after induction cycle BUT - It is of lesser degree / stage / grade & no longer +nt after 6 mon of BCG re- t/t with or without TUR BCG relapse disease Recurrence of tumor after disease free status of 6 mon of BCG  EARLY - < 12 mon INTERMEDIATE – 12- 24 mon LATE - > 24 mon BCG intolerant disease Therapy needed to be terminated due to BCG related serious adverse event before adequate therapy.

77. FACTORS ASSOCIATED WITH RISK OF BCG FAILURE Pathological factors Multifocality, Recurrent tumours, Associated CIS (particularly in the prostatic urethra), Lymphovascular invasion, Detectable disease at 3- month cystoscopy, Depth of lamina propria invasion, Timing of failure (early vs. Late), and Two or more prior courses of BCG Yates D et al. Eur Urol 2012

78. FACTORS ASSOCIATED WITH BCG FAILURE Micrometastatic disease diagnosis is notoriously suboptimal. Patients with NMIBC may already harbour micrometastatic disease. Long- term outcome of patients initially receiving cystectomy at the T1 stage ….. the prevalence of micrometastatic disease often underappreciated. Patard et al. Eur Urol 2002

79. Post Rx Recurrence

80. EAU 2018- Rx options BCG Failure

81. Post Rx Recurrence Two groups of patients presented with recurrence- Who were under observation after initial TURBT— Repeat TURBT f/b intravesical therapy Then followed at 3 months interval. Recurrence following intravesical Rx.— Can be given a second induction course of BCG or mitomycin C. No more than 2 consecutive induction course should be given because such patients will fail 80% of time and presented with rapid disease progression.

82. If after second course of BCG , residual ds is seen at 3month follow- up TURBT If Tis or cTa– Different intravesical agent OR cystectomy. Options for further intravesical treatment after BCG failure include - low dose BCG (1/3 rd dose) plus IFNα- 2B gemcitabine valrubicin docetaxel If high grade cT1 — Cystectomy

83. If after second course of BCG , residual disease is NOT seen at 3month follow- up - - Maintenance therapy with BCG Maintenance therapy for 1 to 3 years. In high risk pts 3 year therapy had better results- Better reduction in local recurrence rate. BUT Not impact progression or survival.

84. Post Rx Recurrence When the disease is found to progress into the muscularis propria (T2 or greater)- Radical cystectomy is indicated.

85. Indications for cystectomy T1 tumors with lymphovascular invasion or micropapillary features Large/diffuse T1 grade 3 tumors are unable to be completely resected Pure squamous cell, or adenocarcinoma histology Prostatic duct/acinar carcinoma in situ (CIS) Women with bladder neck and/or urethral CIS

86. Relative indications for cystectomy Ta or T1 grade 3 associated with Tis; T1b tumors (ie, deep or extensive involvement of lamina propria) Persistent T1 grade 3 tumors identified on re- resection Recurrent or persistent disease within 6 to 12 months of initiating treatment with Bacillus Calmette- Guerin (BCG) Large- volume high- grade disease

87. Patients unsuitable or unwilling for cystectomy* Combination of INF alfa with dose reduced BCG Partial cystectomy Photodynamic therapy Radiation therapy(only for palliative purposes) *most of the therapies are investigational Management of BCG failure

88. Radical cystectomy remains the gold standard for recurrent BCG refractory T1 disease. Justification for this approach- Ten- year cancer- specific survivals is 80% as compared with 50% in patients in whom the cystectomy is performed when the disease progresses to involve the muscularis propria. There is an open protocol RTOG 0926 - evaluating chemoradiation for T1 lesions.

89. When to consider IFN and BCG BCG failure occurred > 1year after BCG treatment Multi-focality Stage: T1 vs Ta Large tumour size: >5cm vs 1cm Age ; 80 yrs vs 39% 2- year CFS vs 61- 70 yrs, 61% CFS

90. Valrubicin FDA- approved treatment of BCG refractory CIS in patients who are not candidates for cystectomy

91. Valrubicin Six weekly instillations of 800 mg intravesical valrubicin 90 patients with recurrent CIS after BCG; 21% had a Complete Response with a median follow- up of 30 months, but only seven (8%) remained disease- free at the end of the study. In all, 56% had a Radical Cystectomy, including 15% with ≥ T3 disease Steinberg et al; The Valrubicin Study Group. J Urol 2000; 163: 761–7

92. GEMCITABINE Dalbagni et al. Phase 2 study of 30 patients with NMIBC who were deemed ‘BCG failures’. The patients received two courses of intravesical gemcitabine twice weekly at a dose of 2000 mg/100 mL for three consecutive weeks. The median follow- up was 19 months. The complete response rate - 50% 1- year recurrence- free survival rate - 21%. 37% ultimately required a radical cystectomy

93. High Risk Management

94. CONCLUSION BCG failure group is a heterogeneous group; no universally agreed definition Combination of clinical, pathological factors to predict BCG response Cystectomy remains the standard of care for high- risk patients who fail BCG therapy Responses to salvage intra- vesical treatments after BCG failure vary; considered investigational There is limited evidence on which option is most beneficial. Induction vs maintenance