Management of Non Muscle Invasive Bladder Cancer

1
Management of Non Muscle Invasive Bladder Cancer

• Manish I. Patel
• Associate Professor, University of Sydney
• And
• Urological Cancer Surgeon
• Westmead and Sydney Adventist Hospital

2
Management of NMIBC

• Tumour resection is important
• Risk Assessment all NMIBC
• When to use Post-operative single instillation of
  chemotherapy
• When to use Delayed Induction Chemotherapy
• BCG or Chemotherapy?
• BCG reduces Progression Rates
• BCG and Maintenance?
• T1G3 and BCG
• T1G3 and Poor risk features
• Algorithm for T1G3 treatment
• Management of CIS only

3
WHO/ISUP Consensus Classification

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

Non-invasive papillary neoplasms
Recurrence Progression Death
0-31 0 0
17-52 0-3 0
34-77 4-10 1-5
43-74 8-35 4-17
Miyamoto et.al. Pathol Int. 2010 60 1-8
4
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, 664-34 2.
Brausi et.al. Eur Urology 2002, 41523-31 3.
Grimm et.al. J Urol 2003 170433
5
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 WL27 PDD 8
• 2 yr recurrence WL 72 PDD60
• 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 69675 4. Babjuk et.al BJUI 200596798
6
1. Staging/Re-resection T1G3

• Single TUR understaging ranges from 20-70.
• Muscularis propria present 141
• Muscularis propria absent 491
• Residual disease remains in 27.2
• Repeat resection decreases recurrences. 3
• In a randomised study of TURMMC vs TURMMCreTUR
• 3 yrs rec-free survival improved 37 to 69.
• Re-resection is prognostic. 4
• Residual T1 disease 82 muscle invasion _at_ 5yrs.
• Residual T0/CIS/Ta 19 muscle invasion _at_ 5 yrs

1Herr et.al. BJU Int 20018883685. 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
17775
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2. Assessment of RiskEORTC Risk Assessment
Calculator
Recurrence Recurrence Recurrence 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 Progression Progression 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
8
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 1712186
9
3. Post-op Single Instillation Chemotherapy?

• Single tumours (n839)
• Rec 47 TUR vs 36 Chemo

Sylvester J Urol 2004 1712186
10
3. Post-op Single Instillation Chemotherapy?

• Multiple tumours (n111)
• Rec 82 TUR vs 65 Chemo

Sylvester J Urol 2004 1712186
11
3. Single Instillation Chemotherapy

• Which chemo is best?
• Epirubicin and MMC are equivalent.

12
3. Post-op Single Instillation ChemotherapyConclu
sion

• 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 lt 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
13
4. Adjuvant Therapy For Intermediate and High
Risk NMIBC

• For patients at Intermediate or High Risk single
  instillation chemo is inadequate (gt65
  recurrence).
• Choice of Chemotherapy or BCG depends on the risk
  of recurrence and progression.

14
4. Delayed Induction Chemotherapy TURB vs
TURBMultiple Chemo

• Meta-analysis of 11 randomised trials, 3703
  patients.
• Mainly intermediate risk
• TURBT vs TURBT Short term Chemo (lt2 months)
• 1258 patients
• OR for treatment0.70 0.55-0.90 (plt0.05)
• TURBT vs TURBT 1 year Chemo
• 1721 patients
• OR for treatment 0.65 0.46-0.80 (plt0.05)
• TURBT vs TURBT 3 year Chemo
• 1371 patients
• OR for treatment 0.50 0.40-0.62 (plt0.05)

Huncharek J Clinical Epidemiology 2000, 53 676
15
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
  (plt0.05)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 53709 2Tolley J
Urol 1996 155 1233,
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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, 93597
17
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
18
5. BCG vs Mitomycin C Individual Patient
Meta-analysis
Not Sig
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6. BCG Reduces the Risk of Progression!Meta-analy
sis

• 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
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6. BCG Reduces the Risk of Progression!
Sylvester J Urol 2002 168 1964
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6. The Strain of BCG Does Not Matter
Sylvester J Urol 2002 168 1964
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7. Maintenance is Essential to Reduce Progression
Sylvester J Urol 2002 168 1964
23
7. Randomised Study of BCG Maintainence

• Randomised Phase III
• High Risk NMIBC
• N384
• 6 weeks induction and percutaenous
• Randomised to Maintainence or no Maintenance
• Maintenance 3 instillations _at_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
Survival 5 yrs 78 83 NS
Only 16 of 243 patients on Main. Received all
maint. schedules
Lamm J Urol 2000 163 1124
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7. Optimal BCG Maintainence Schedule

• Clear that the full Lamm protocol may not be
  required.
• Only 16 finished the full course
• lt50 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.

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Long Term Natural History of High Grade Tumours

• 86 men with high grade disease
• 81 CIS and 44 with T1 disease
• Treated with TURBTBCG
• 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 1997158, 62
26
8. BCG for T1G3

• Hampered by randomised studies lumping all high
  risk together.

Kulkarni et.al. Eur Urol 2010 57 60-70
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8. Early BCG Failure/Refractory T1G3

• If
• Disease is growing at 3m CE Cystectomy.
• Disease is still present at 6m CE
  Cystectomy.

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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 1987137220 2. Raj
et.al. J Urol. 2007 1771283
29
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 FUCE
• 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
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9. Risk Stratification High risk T1G3

• Risk Factors (HR- progression)1
• CIS (3.4)
• Multifocality (1.7)
• Hydronephrosis (2.4)
• Tumourgt3cm (1.9-3.1)
• T1a vs T1b/c (6.9)
• Tumour _at_3m CE (4.8)

• Denzinger et.al. 20082
• 105 High risk T1G3
• 2/3 (CIS, gt3cm, 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
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10. Algorithm for Treatment of T1G3
32
11. How To Manage CIS

• Untreated natural history 50 progression _at_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)

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11. How To Manage CIS-BCG
35
Progression risk 14 _at_ 2.5 yrs
Sylvester et.al. JUrol 2002, 1681964
34
11. CIS BCG Failure

• Worsening disease _at_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.

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Final Recommendations

1. Post-op single instillation
2. All low risk bladder tumours
3. Possibly all NMIBC
4. Delayed induction chemotherapy
5. Intermediate risk
6. 6 weeks appears OK
7. BCG
8. Intermediate and high risk bladder tumours
9. Need MAINTAINENCE for reduced recurrence and
   progression
10. T1G3
11. Re-resect
12. Consider Cyctectomy for high risk.
13. BCG MAINTAINENCE
14. Low threshold for cyctectomy in
    resistant/refractory disease.