Management of Non Muscle Invasive Management of Non Muscle Invasive Bladder CancerBladder Cancer

Manish I. PatelManish I. PatelAssociate Professor, University of SydneyAssociate Professor, University of Sydney

AndAndUrological Cancer SurgeonUrological Cancer Surgeon

Westmead and Sydney Adventist HospitalWestmead and Sydney Adventist Hospital

Management of NMIBC1. Tumour resection is important2. Risk Assessment all NMIBC3. When to use Post-operative single instillation of

chemotherapy4. When to use Delayed Induction Chemotherapy5. BCG or Chemotherapy?6. BCG reduces Progression Rates7. BCG and Maintenance?8. T1G3 and BCG9. T1G3 and Poor risk features10.Algorithm for T1G3 treatment11. Management of CIS only

WHO/ISUP Consensus Classification• 2004 WHO/ISUP classification• Aimed to improve interobserver reproducibility

Recurrence Progression Death

0-31% 0% 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. 2010 60: 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, 66:4-34 2. Brausi et.al. Eur Urology 2002, 41:523-31 3. 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.3 301 pts randomised to WL or PDD TURBT

• Median follow up 84 months• Tumor recurrences WL: 44% PDD: 16%

– Babjuk et.al.4 122 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 2010 105, supp 2: 2 3. Denzinger et.al. Urology 2007; 69:675 4. 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 invasion @ 5yrs.– Residual T0/CIS/Ta= 19% muscle invasion @ 5 yrs

1Herr et.al. BJU Int 2001;88:83–685. 2 Jakse et.al. Eur Urol 2004, 45: 539-46 3Divrik et.al. J Urol 2006; 175: 1258 4 Herr et.al J Urol 2007; 177:75

2. Assessment of RiskEORTC Risk Assessment Calculator

Recurrence

Score 1 yr (%)

5 yr (%)

Risk Group

0 15 31 Low

1-4 24 46 Int

5-9 38 62 Int

10-17 61 78 High

Progression

0 0.2 0.8 Low

2-6 1 6 Int

7-13 5 17 High

14-23 17 45 High

http://www.eortc.be/tools/bladdercalculator

3. Who Benefits From Post-op Single Instillation Chemotherapy?

• Meta-analysis 2004• 7 randomised trials• 1981-1994• Median FU 3.4 years• Patients tended to be

low risk– 89% primary

tumours– 84% single tumours– 10% G3

Sylvester J Urol 2004 171:2186

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

Sylvester J Urol 2004 171:2186

3. Post-op Single Instillation Chemotherapy?

• Multiple tumours (n=111)• Rec: 82% TUR vs 65% Chemo

Sylvester J Urol 2004 171:2186

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

3. Post-op Single Instillation ChemotherapyConclusion

• 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 2008 53: 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 [0.55-0.90] (p<0.05)

• TURBT vs TURBT+ 1 year Chemo– 1721 patients– OR for treatment = 0.65 [0.46-0.80] (p<0.05)

• TURBT vs TURBT+ 3 year Chemo– 1371 patients– OR for treatment= 0.50 [0.40-0.62] (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

1Sylvester Eur Urology 2008 53:709 2Tolley J Urol 1996 155: 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 CIndividual 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 2009 56: 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 2002 168: 1964

6. BCG Reduces the Risk of Progression!

Sylvester J Urol 2002 168: 1964

6. The Strain of BCG Does Not Matter

Sylvester J Urol 2002 168: 1964

7. Maintenance is Essential to Reduce Progression

Sylvester J Urol 2002 168: 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 instillations

@3m, 6m, 12m, 18m, 24m, 30m, 36m.

• FU= 120m

No Maint

Maint p

Rec free survival

36m 77m Sig

“Worsening free survival”% 5yrs

70 76 Sig

Survival5 yrs

78 83 NS

Lamm J Urol 2000 163: 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 (1st 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.

• 3rd cycle of BCG- NO– 6% response.

1. Brake et.al. Urology; 1987;137:220 2. 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.1

• 9-18% 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: 822 2. 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 (1.9-3.1)• T1a vs T1b/c (6.9)• Tumour @3m CE (4.8)

• Denzinger et.al. 20082

• 105 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: 60-70 2.Denzinger et.al. Eur Urol 2008; 53: 146

10. Algorithm for Treatment of T1G3

11. How To Manage CIS

• Untreated natural history: 50% progression @5yrs.• 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– 2nd 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, 168:1964

35% Progression risk 14% @ 2.5 yrs

11. CIS: BCG Failure

• Worsening disease @3m or refractory disease at 6m mandates cyctectomy.

• If CIS recurs after an initial CR try induction BCG again (provided not had mantainance or 2nd induction).-approx 40-50% 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 Recommendations1. Post-op single instillation

1. All low risk bladder tumours2. Possibly all NMIBC

2. Delayed induction chemotherapy1. Intermediate risk2. 6 weeks appears OK

3. BCG1. Intermediate and high risk bladder tumours2. Need MAINTAINENCE for reduced recurrence and progression

4. T1G31. Re-resect2. Consider Cyctectomy for high risk.3. BCG + MAINTAINENCE4. Low threshold for cyctectomy in resistant/refractory disease.