latest developments in intravesical therapy

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

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


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


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?

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

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


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


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


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

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

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


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

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