Transcript Document

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
Non-invasive papillary neoplasms
Miyamoto et.al. Pathol Int. 2010 60: 1-8
Recurrence
Progression
Death
0-31%
0%
0%
17-52%
0-3%
0%
34-77%
4-10%
1-5%
43-74%
8-35%
4-17%
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
White
– 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
Blue
• 12wk recurrence: WL:27% PDD: 8%
• 2 yr recurrence: WL: 72% PDD:60%
• QoL or Economic impact unproven
• Possible roles
Tumour
– Resection of all new tumours,
– Follow-up of CIS
– Positive UC, but negative CE
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
et.al. J Urol 2006; 175: 1258 4 Herr et.al J Urol 2007; 177:75
3Divrik
2. Assessment of Risk
EORTC 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 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 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 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 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
•
•
•
•
No
Maint
Randomised Phase III
Maint
High Risk NMIBC
Rec free
36m
77m
survival
N=384
“Worsening free
70
76
6 weeks induction and
survival”
percutaenous
% 5yrs
• Randomised to
Survival
78
83
5 yrs
Maintainence or no
Maintenance
• Maintenance= 3 instillations
@3m, 6m, 12m, 18m, 24m, Only 16% of 243 patients on
Main. Received all maint.
30m, 36m.
schedules
• FU= 120m
Lamm J Urol 2000 163: 1124
p
Sig
Sig
NS
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
35%
Sylvester et.al. JUrol 2002, 168:1964
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 4050% 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.