Management of Non Muscle Invasive Bladder Cancer Manish I. Patel Associate Professor, University of Sydney And Urological Cancer Surgeon Westmead and Sydney Adventist Hospital

Management of NMIBC 1.Tumour resection is important 2.Risk Assessment all NMIBC 3.When to use Post-operative single instillation of chemotherapy 4.When to use Delayed Induction Chemotherapy 5.BCG or Chemotherapy? 6.BCG reduces Progression Rates 7.BCG and Maintenance? 8.T1G3 and BCG 9.T1G3 and Poor risk features 10.Algorithm for T1G3 treatment 11. Management of CIS only

WHO/ISUP Consensus Classification 2004 WHO/ISUP classification Aimed to improve interobserver reproducibility RecurrenceProgressionDeath 0-31%0% 17-52%0-3%0% 34-77%4-10%1-5% 43-74%8-35%4-17% Non-invasive papillary neoplasms Miyamoto et.al. Pathol Int : 1-8

1.Tumour Resection Is Important Staged resection technique is important. 1 Quality of TUR very important for recurrence. 2 – In 2410 EORTC patients in 7 phase III intravesical adjuvant trials – Recurrence at 3m CE varied from 7.6% to 40%. – After controlling for prognostic factors- believed to be due to surgeon skill. Relook CE is indicated in any patient in whom there is doubt on complete resection. – Repeat resection can decrease recurrence rates from 61% to 32% 3 1. Kirkali et.al. Urology 2005, 66: Brausi et.al. Eur Urology 2002, 41: Grimm et.al. J Urol 2003; 170:433

1. Photodynamic Diagnosis Improves detection of tumours – Detects approx 17% extra tumours over WL alone 1. – CIS: PPD detection 91-97%, WL alone 23-68% 2. Improves Recurrence free survival – Denzinger et.al pts randomised to WL or PDD TURBT Median follow up 84 months Tumor recurrences WL: 44% PDD: 16% – Babjuk et.al pts randomised to WL or PDD 12wk recurrence: WL:27% PDD: 8% 2 yr recurrence: WL: 72% PDD:60% QoL or Economic impact unproven Possible roles – Resection of all new tumours, – Follow-up of CIS – Positive UC, but negative CE White Blue Tumour 1. Stenzl et.al EAU 2009, 2. Bunce et.al. BJUI , supp 2: 2 3. Denzinger et.al. Urology 2007; 69: Babjuk et.al BJUI 2005;96:798

1. Staging/Re-resection: T1G3 Single TUR understaging ranges from 20-70%. – Muscularis propria present: 14% 1 – Muscularis propria absent: 49% 1 Residual disease remains in 27%. 2 Repeat resection decreases recurrences. 3 – In a randomised study of TUR+MMC vs TUR+MMC+reTUR – 3 yrs rec-free survival improved 37% to 69%. Re-resection is prognostic. 4 – Residual T1 disease= 82% muscle 5yrs. – Residual T0/CIS/Ta= 19% muscle 5 yrs 1 Herr et.al. BJU Int 2001;88:83– Jakse et.al. Eur Urol 2004, 45: Divrik et.al. J Urol 2006; 175: Herr et.al J Urol 2007; 177:75

2. Assessment of Risk EORTC Risk Assessment Calculator Recurrence Score1 yr (%) 5 yr (%) Risk Group 01531Low Int Int High Progression Low 2-616Int High High

3. Who Benefits From Post-op Single Instillation Chemotherapy? Meta-analysis randomised trials Median FU 3.4 years Patients tended to be low risk – 89% primary tumours – 84% single tumours – 10% G3 Sylvester J Urol :2186

3. Post-op Single Instillation Chemotherapy? Single tumours (n=839) Rec: 47% TUR vs 36% Chemo Sylvester J Urol :2186

3. Post-op Single Instillation Chemotherapy? Multiple tumours (n=111) Rec: 82% TUR vs 65% Chemo Sylvester J Urol :2186

3. Single Instillation Chemotherapy Which chemo is best? Epirubicin and MMC are equivalent.

3. Post-op Single Instillation Chemotherapy Conclusion Decreases recurrences by 39%. – Appears valid for single as well as multiple tumours Very little morbidity Economic viability – 11.7 TURs saved per 100 low risk patients – NNT is 8.5 – Cost of 8.5 instillations is < one TUR (all assoc costs) Give to all tumours resected. – Definitely all low risk (Int and High Risk debatable) Sylvester Eur Urology : 709

4. Adjuvant Therapy For Intermediate and High Risk NMIBC For patients at Intermediate or High Risk single instillation chemo is inadequate (>65% recurrence). Choice of Chemotherapy or BCG depends on the risk of recurrence and progression.

4. Delayed Induction Chemotherapy TURB vs TURB+Multiple Chemo Meta-analysis of 11 randomised trials, 3703 patients. Mainly intermediate risk TURBT vs TURBT+ Short term Chemo (<2 months) – 1258 patients – OR for treatment=0.70 [ ] (p<0.05) TURBT vs TURBT+ 1 year Chemo – 1721 patients – OR for treatment = 0.65 [ ] (p<0.05) TURBT vs TURBT+ 3 year Chemo – 1371 patients – OR for treatment= 0.50 [ ] (p<0.05) Huncharek J Clinical Epidemiology 2000, 53: 676

4. Delayed Induction Chemotherapy In low risk patients, can better results be obtained with delayed multiple instillations vs single post-op? – No: 3 randomised epirubicin trials, only one shows a small sig difference in recurrence. 1 After one instillation, can further chemo reduce recurrence in pts with multiple (intermediate risk) tumours? – Yes: MRC trial, 4 additional three monthly MMC given to one arm. – Recurrence can be reduced from 70% to 50% (p<0.05) 2 Is single instillation still important if long term chemo is planned? – Six months chemo: Yes: One randomised trial rec 43% (immed instillation) vs 55% (no-immed. Instillation) 1 – Twelve months chemo: No: 4 trials, combined- no difference. 1 1 Sylvester Eur Urology :709 2 Tolley J Urol : 1233,

4. Delayed Induction Chemotherapy Improving MMC efficacy Increasing MMC drug concentration from 20mg/20ml to 40mg/20ml and Fasting to decrease Urine output and Urine alkalinisation to stabilise drug Resulted in recurrence free time at 5 years to increase from 41% to 51%. Au JNCI 2001, 93:597

5. BCG vs Mitomycin C Individual Patient Meta-analysis Nine Randomised trials 2820 patients MMC dose 20-40mg Some trials included BCG maintanence Median FU 4.4 years 71% primary 54% Ta 43% T1 3.4% Low Risk 74% Intermediate Risk 23% High Risk 7% prior chemotherapy Malstrom Eur Urology : 247

5. BCG vs Mitomycin C Individual Patient Meta-analysis Not Sig

6. BCG Reduces the Risk of Progression! Meta-analysis 24 randomised trials 5456 patients Treatment= BCG + M Control = TUR or Chemo Median FU 2.5 years 82% papillary only 50% T1 55% G2 8% G3 77% Maintainence Sylvester J Urol : 1964

6. BCG Reduces the Risk of Progression! Sylvester J Urol : 1964

6. The Strain of BCG Does Not Matter Sylvester J Urol : 1964

7. Maintenance is Essential to Reduce Progression Sylvester J Urol : 1964

7. Randomised Study of BCG+ Maintainence Randomised Phase III High Risk NMIBC N=384 6 weeks induction and percutaenous Randomised to Maintainence or no Maintenance Maintenance= 3 6m, 12m, 18m, 24m, 30m, 36m. FU= 120m No Maint Maintp Rec free survival 36m77mSig “Worsening free survival” % 5yrs 7076Sig Survival 5 yrs 7883NS Lamm J Urol : 1124 Only 16% of 243 patients on Main. Received all maint. schedules

7. Optimal BCG Maintainence Schedule Clear that the full Lamm protocol may not be required. Only 16% finished the full course <50% completed 3 cycles (1 st year of maintainence) No analysis of the best protocol. Various protocols ranging from 1/month for 12 m to the full Lamm protocol.

Long Term Natural History of High Grade Tumours 86 men with high grade disease – 81% CIS and 44% with T1 disease Treated with TURBT+BCG Median follow-up 15.3 years At 15 years: 34% were dead from bladder cancer. 53% disease stage progressed. 31% progressed AFTER 5 years. 36% eventually underwent cystectomy. Cookson et.al. JUrol 1997:158, 62

8. BCG for T1G3 Hampered by randomised studies lumping all high risk together. Kulkarni et.al. Eur Urol 2010; 57: 60-70

8. Early BCG Failure/Refractory: T1G3 If – Disease is growing at 3m CE Cystectomy. – Disease is still present at 6m CE Cystectomy.

8. Late BCG failures: T1G3 Initial CR to BCG at 6m but recurrence after. Approx 1/3 are muscle invasive cystectomy If rec is CIS or Ta consider re-induction BCG. 1 – 79% recurrence free. If rec is T1 cystectomy. 2 – Second course of BCG – 71% progression to muscle invasion. – 48% death from bladder cancer. 3 rd cycle of BCG- NO – 6% response. 1. Brake et.al. Urology; 1987;137: Raj et.al. J Urol. 2007; 177:1283

9. Immediate Cystectomy Immediate cystectomy for T1G3 – DSS 80-90% Approx 13% will still be understaged following re-TUR % will be lymph node positive. 2 No need for frequent FU+CE Perioperative morbidity and mortality (1-6%) QoL impact. Overtreatment in 50% cases. 1. Dalbagni et.al. Urology 2002; 60: Kulkarni et.al. Eur Urol 2010; 57: 60-70

9. Risk Stratification: High risk T1G3 Risk Factors (HR- progression) 1 CIS (3.4) Multifocality (1.7) Hydronephrosis (2.4) Tumour>3cm ( ) T1a vs T1b/c (6.9) CE (4.8) Denzinger et.al High risk T1G3 – 2/3 (CIS, >3cm, multifocal) 54 immediate cystectomy – 10yr DSS 78% 51 conservative – All had early cystectomy – Median 11.2m – 10yr DSS 51% 1. Kulkarni et.al. Eur Urol 2010; 57: Denzinger et.al. Eur Urol 2008; 53: 146

10. Algorithm for Treatment of T1G3

11. How To Manage CIS Untreated natural history: 50% When in conjunction with HG T1 – even higher. 14% rec in upper tracts and 23% in prostate. Treatment Intravesical BCG (induction 6 weeks) – 3 month response rate= 60-70% In the event of positive cytology or persistent CIS (without worsening disease) at 3 months – 2 nd course BCG (EAU recommendation) – Maintanence BCG (SWOG recommendation) – 43% CIS at 3m decreased to 20% at 6m with no further Tx (Herr JUrol 2003, 169: 1706)

11. How To Manage CIS-BCG Sylvester et.al. JUrol 2002, 168: % Progression risk 2.5 yrs

11. CIS: BCG Failure Worsening or refractory disease at 6m mandates cyctectomy. If CIS recurs after an initial CR try induction BCG again (provided not had mantainance or 2 nd induction).-approx % response. Experimental Options Intravesical Gemcitabine: 7/14 BCG refractory pts had CR. 1 pt developed muscle invasive disease. (Dalbagni 2002) Intravesical Valrubicin: 19/90 BCG resistant or recurrent CIS has CR. 44/90 underwent cystectomy, and 6 had pT3 disease.

Final Recommendations 1.Post-op single instillation 1.All low risk bladder tumours 2.Possibly all NMIBC 2.Delayed induction chemotherapy 1.Intermediate risk 2.6 weeks appears OK 3.BCG 1.Intermediate and high risk bladder tumours 2.Need MAINTAINENCE for reduced recurrence and progression 4.T1G3 1.Re-resect 2.Consider Cyctectomy for high risk. 3.BCG + MAINTAINENCE 4.Low threshold for cyctectomy in resistant/refractory disease.