Latest Developments in Intravesical Therapy
Hugh Mostafid
Consultant Urologist
North Hampshire Hospital
Basingstoke
Intravesical therapy in 2011
Trends• Treatment based on risk groups• Focus on intermediate group• Maintenance intravesical chemotherapy• Reduction of side-effects• Device assisted therapy• BCG failures • New agents/concepts
Intravesical therapy in 2011
Trends• Treatment based on risk groups• Focus on intermediate group• Maintenance intravesical chemotherapy• Reduction of side-effects• Device assisted therapy• BCG failures • New agents/concepts
Treatment based on risk groups
% of total
Recurrence Progression
1 yr 5 yr 1yr 5yr
Low Risk
50 15-24 31-46 <1 1-6
Intermediate Risk
35 24-38 46-62 <1-5 1-17
High Risk
15 24-61 46-78 1-17 6-45
Limitations
• Predates BCG maintenance
• No re-TURBT
• 20% had no intravesical therapy
• <10% received immediate instillation
EORTC risk tables Sylvester 2006
Intravesical therapy in 2011
Trends• Treatment based on risk groups• Focus on intermediate group• Reduction of side-effects• Maintenance intravesical chemotherapy• Device assisted therapy• BCG failures • New agents/concepts
Intermediate risk group
% of total
Recurrence Progression
1 yr 5 yr 1yr 5yr
Low Risk
50 15-24 31-46 <1 1-6
Intermediate Risk
35 24-38 46-62 <1-5 1-17
High Risk
15 24-61 46-78 1-17 6-45
Ta-T1,G1-2
Multifocal
>3cm diameter
Recurrence rateProgression rate ?
Intermediate risk group
Why the interest in the intermediate group?
• Single instillation is suboptimal• Chemo or BCG?
• If chemo, optimal schedule unknownX6 or maintenance (how long?)
• If BCG, how to reduce side-effectsHow long maintenance?
Intravesical therapy in 2011
Trends• Treatment based on risk groups• Focus on intermediate group• Maintenance intravesical chemotherapy• Reduction of side-effects• Device assisted therapy• BCG failures • New agents/concepts
Long term maintenance chemotherapy in Intermediate risk group
• Long term chemotherapy maintenance Friedrich 2007
• 495 pts
• BCGx6 vs. MMCx6 vs. MMC 3yrs
• MMC 3yrs reduced 3yr RR to 14%• Toxicity acceptable
But• Only 20mg MMC used• No immediate single dose• Only 8% finished maintenance• No data on progression
• But short term intensive Rx over < 1 yr may provide as good results as long term chemoTolley 1996,Schwaibold 1997, Koga 2004, Kuroda 2004
• Confounding effect of whether or not one immediate dose was given Bouffioux 1995, Ali-el-Dein 1997
• Carcinogenic effect of long-term chemoRx
Intravesical therapy in 2011
Trends• Treatment based on risk groups• Focus on intermediate group• Maintenance intravesical chemotherapy• Reduction of side-effects• Device assisted therapy• BCG failures • New agents/concepts
BCG maintenance
• Optimal therapy for reducing progression rateSylvester 2002
But• 5% stop during induction• 20% stop during maintenance
Reduced toxicity desirable
BCG Toxicity
Groups NMedian followup
Oncological outcome
Toxicity
90.008
2002
81mg vs. 27mg BCG Connaught
500 69
No diff in rec. or prog except for multifocal
tumours. Trend towards lower RR with
full dose in high risk tumours
1/3 dose toxicity lower
95.012
2005 81mg vs. 27mg in high risk tumours
155 61
1/3 dose as effective as full dose for high risk disease
1/3 dose toxicity lower
95.011
2007
27mg vs. 13.5.mg vs. 30
mg MMC intermediate
risk
430 53
1/3 dose is minimum
effective dose for int risk
1/3 and 1/6 dose have
same toxicity
Spanish CUETO group
Low Dose BCG vs. MMC
CUETO 95011 Ojea 2007
• Significantly longer DFI for BCG 27mg versus MMC 30 mg• No significant difference in progression rate or cancer specific
survival• Local and systemic toxicity higher for both BCG groups
• BUT• Only 30mg MMC used 12 Instillations over 18 weeks• No immediate single dose of chemo
BCG Toxicity
EORTC 30962
1/3 vs. full dose
1 year vs. 3 years maintenance
• 1355 patients recruited, closed in 2005• Last patients finish 3 yrs maintenance in 3/08
• First report, on toxicity data expected in late 2008
EORTC
EORTC 30911
• 3 yrs maintenance Epirubicin vs. BCG Sylvester 2001
• Long term results to be presented at EAU 2008
Reducing BCG side-effects
Reducing the number of instillations of BCG maintenance vs. reducing the dose
• Proposed EORTC phase II study
Intravesical therapy in 2011
Trends
• Treatment based on risk groups• Focus on intermediate group Maintenance
intravesical chemotherapy• Reduction of side-effects• Device assisted therapy• BCG failures• New agents/concepts
High Risk group
% of total
Recurrence Progression
1 yr 5 yr 1yr 5yr
Low Risk
50 15-24 31-46 <1 1-6
Intermediate Risk
35 24-38 46-62 <1-5 1-17
High Risk
15 24-61 46-78 1-17 6-45
G3T1
Multifocal
>3 recurrences in 24 months
CIS
progressionside-effects acceptable
Device assisted therapy
•ElectroMotive Drug Administration
BCG once a week for 6 weeks (n=105) BCG infused once a week for 2 weeks, followed by 40 mg EMDA MMC for three weeks (n=107)
212 Stage pT1 patients
BCG once a month for 10 months 40 mg EMDA MMC once a month for 2 months followed by BCG once a month as 1 cycle, for 3 cycles
DiStasi 2006
EMDA MMC/BCG vs BCG
‘BCG-induced inflammation might increase the permeability of the bladder mucosa such that mitomycin can reach the target tissue more easily and exert its anticancer effect.’
DiStasi 2006
EMDA MMC + BCG
BCG Difference
Disease free interval (months)
69 21 48 p=0.0012
Recurrence %
41.9 57.9 16 p=0.0012
Progression %
9.3 21.9 12.6 p=0.004
Overall mortality %
21.5 32.4 10.9 p=0.045
Disease-specific mortality %
5.6 16.2 10.6 p=0.01
Intravesical therapy in 2011
Trends• Treatment based on risk groups• Focus on intermediate group• Maintenance intravesical chemotherapy• Reduction of side-effects• Device assisted therapy• BCG failures• New agents/concepts
Thermochemotherapy
• Effective as prophylaxis and ablative Rx for G3 tumours
• Effective in BCG failures:
90 pts inc. 41 BCG failures• 1 yr RR: 14% 23%• 2 yr RR: 25% 41%• No progression
• CIS: 57 pts inc 40 BCG failures: 94% initial CR, 30% 1yr RR
• Phase III study recruiting: TCT vs. BCG in high risk NMIBC
Gofrit 2004
Van der Heijden 2004
Witjes EAU 2007
TCT vs EMDA vs MMC vs BCG
• Neo-adjuvant Rx of a single recurrent tumour
CR
TCT 66%
EMDA MMC 40%
MMC 28%
Colombo 2001
• High risk NMIBC
6 mo.CR
MMC 31%
EMDA MMC 58%
BCG 64%
Di Stasi 2003
Intravesical therapy in 2011
Trends• Treatment based on risk groups• Focus on intermediate group• Maintenance intravesical chemotherapy• Reduction of side-effects• Device assisted therapy• BCG failures• New agents/concepts
BCG failures
BCG combined with Interferon- O’Donnell 2004 Joudi 2006
• 467 BCG intolerant or failures received dose BCG+IFN-
• 536 BCG naive pts received standard BCG+IFN-
• 45% of BCG failures remained disease free at median follow-up of 24-months
• 4% progressed to T2
Intravesical therapy in 2011
Trends• Treatment based on risk groups• Focus on intermediate group• Maintenance intravesical chemotherapy• Reduction of side-effects• Device assisted therapy• BCG failures• New agents/concepts
New Agents - Phase I studies
Pirirubicin Okamura 2002
Valrubicin Steinberg 2000
Vinorelbine Bonfil 2001
Meglumine -linolenic acid Harris 2002
Recombinant human interleukin-12 Weiss 2003
Suramin Ord 2005
Docetaxel McKiernan 2006
Ethics of phase II studies in high risk BCG failuresCosts of phase III studies
New Agents
Gemcitabine Lilly Pharmaceuticals
Phase II marker lesion studies • 6 weeks instillations: 56% CR Gontero 2004
• In total 6 phase II studies, total of 184 pts, CR 44-66%
Phase III studies• German co-operative group, immediate post-op gemcitabine
Results awaited• SWOG study, target 340 patients, starting soon
• No plans to license gemcitabine for intravesical use(coming off patent)
New Agents
Apaziquone (Eoquin, EO9) Spectrum Pharmaceuticals
• Indolequininone derivative of MMC• Both Eoquin and MMC require activation by cellular reductase
enzymes
• Phase II study in 46 patients: 6 instillations produced 67% CR of
marker lesion
Currently:
• RCT of 1 immediate dose Eoquin vs. nothing (U.S)
• Adjuvant Eoquin for pts with high risk BCG refractory NMIBC
Van der Heijden 2006
New Agents
Urocidin (MCC) Bioniche Life Sciences
• A formulation of Mycobacterial Cell Wall-DNA
Complex (MCC)
• 2 Phase III trials underway: (U.S)
- 2nd line therapy in BCG failures
- Urocidin vs. BCG as first-line therapy in NMIBC
New Agents
Keyhole limpet hemocyanin (KLH)
• A high-molecular-weight protein antigen collected from the haemolymph of the sea mollusk Megathura crenulata
• Powerful non-specific immune response modifier• Small number of long term remissions in CIS Jurincic-Winkler 2000
• Study of KLH vs. MMC just finishing (P.I. : Prof Witjes)
New concepts
Photodynamic therapy Bader EAU 2007
• H-ALA (Hexvix) Protoporphyrin IX (PPIX) intracellularly• PPIX is a photosensitiser
• 14 pts with High grade NMIBC• 3 PDT sessions using a high power white light source• Technically feasible and safe
Low Risk group
% of total
Recurrence Progression
1 yr 5 yr 1yr 5yr
Low Risk
50 15-24 31-46 <1 1-6
Intermediate Risk
35 24-38 46-62 <1-5 1-17
High Risk
15 24-61 46-78 1-17 6-45
Single TaG1, <3cm
Recurrence rate
Side effects not justified
New concepts: Low risk group
• Single immediate instillation following TURBT is sufficient treatment Sylvester 2006
• Watchful waiting at recurrence is safeSoloway 2003, Gofrit 2006, Miller 2007
• PBR tariff for cystodiathermy - TURBT: £730 - £1502
Chemoresection?
Conclusions
• Superficial NMIBC Risk groups
• Optimal Rx for intermediate risk group?
• Reduce toxicity of BCG
• Optimal Rx for BCG failures
• Development of new compounds/DAT/concepts