Intravesical Therapy

Old trials, new agents and new approaches

Hugh Mostafid

North Hampshire Hospital, Basingstoke

What can the old trials tell us?

Outcome

• Recurrence

• Progression

Factors which affect it

• Single Dose• Timing• Induction• Maintenance• Which Drug• Drug optimisation

What can the old trials tell us?

Single Dose

• Meta-analysis of 7 RCTs• 1476 pts with IC within 24 hours

• Single instillation reduced recurrence rate from 48.4 to 36.7%

• No difference between MMC, Epirubicin and Doxorubicin

Sylvester 2004

Timing• Recurrence lower if given within 6 hours cf. 24 hours

• If instillation > 24 hours, recurrence rate is doubledKaasinen 2002

Survey of UK intravesical chemotherapy practice

527 consultant questionnaires produced 313 evaluable responses

• 244 (82%) advocated single dose of MMC• 155 (64%) use within 24 hours• 10 (4%) use immediately

69 Don’t give single dose 84 give single dose > 24 hours

• 23 (8%) use MMC as 1st line for G3 pT1• 20 (7%) use MMC as 1st line for CIS

Clarke 2006

153 consultants outside EAU guidelines

What can the old trials tell us?

EAU guidelines 2006 • Unnecessary for solitary G1/2 pTa tumours (50%)

• Necessary for large (>3 cm) and mutifocal tumours (35%)

• High risk tumours (G3 pT1 , CIS) require BCG (15%)

Based on meta-analysis of EORTC and MRC trials Pawinski 1996

Induction therapy (6 courses)

What can the old trials tell us?

Maintenance therapy

Meta-analysis of 9 RCTs

• 1774 pts, maintenance MMC• Recurrence rate (RR) 38% with maintenance cf. 54% in TURBT only group Nilsson 2001

2 EORTC trials (MMC and Doxorubicin)

• Monthly instillations for 6 or 12 months• No effect on RR if 1st instillation given after TURBT Bouffioux 1995

To date no prospective studies show a difference in RR or time to recurrence between induction and maintenance Rx

Malmstrom 2004

What can the old trials tell us?

Which Drug?

No differenceThiotepa 44%Adriamycin 39%Mitomycin C 36%Epirubicin 39% Kamat 2000

MMC superior?• Stratified data from meta-analysis of 8 RCTs comparing

intravesical chemotherapy with BCGHuncharek 2004

Recurrence rate

Optimising intravesical chemotherapy

• RCT 119 pts: 6/52 Standard vs Optimised RxNaHCO3 to urine pH

Overnight fasting to U.O

Bladder residual emptied

40 mg MMC given

• At 5yrs

Time to recurrence % Recurrence free

Optimized MMC 29.1 41

Standard MMC 11.8 24.6

Au 2001

MMC optimized treatment

Optimising intravesical chemotherapy

Turning the patient?

• No mention in any trial, paper, abstract,review or guideline

• Often difficult to achieve practically

Better to focus on

• Timing of single dose

• Maintenance instillations Fasting for 6 hours

Empty bladder residual

(Alkalinisation of urine)

Optimising intravesical chemotherapy

Synergistic effect?

• 137 pts with G3pT1

• Combined MMC and Epirubicin maintenance

• Significantly lower RR than MMC, doxorubicin or Epirubicin

aloneSeretta

2004

What can the old trials tell us?

1. Does intravesical chemotherapy alone prevent progression?

No - EORTC / MRC meta-analysis Pawinski 1996

No proof that any chemotherapeutic agent alone, either as early instillation or maintenance prevents progression or improves

disease-specific survivalOkeke 2005

Progression

What can the old trials tell us?

2. Is BCG superior to intravesical chemotherapy at preventing progression?

Only if maintenance BCG given:Meta-analysis of 24 RCTs, 4863 patients Sylvester 2002

Meta-analysis of 9 RCTs, 2410 patients Bohle 2004

Differences due to failure to control for prior chemotherapy RxMeta-analysis of 8 RCTs, 2427 patients Huncharek 2004

Progression

Mode of action

• Prevent reseeding Zincke 1983

• Destroys residual tumour- ‘Chemoresection’ Masters 1999

• Not able to compensate for incomplete resection Divrick 2006

• May provoke significant alterations in the normal

urothelium which could be mistaken for malignant

lesions Mazzucchelli 2005

Complications of Intravesical Chemotherapy

Adverse effects • Chemical cystitis 40% • Allergic skin reactions 16%

Systemic complications• Severe Myelosuppression: A few reported cases after v.high

doses or early instillation after v.large resection area Thrasher 1992

• Maintenance has higher incidence of adverse events owing to higher cumulative doses Schenkman 2004

Complications of Intravesical Chemotherapy

Severe local complications after early instillation of MMC• 6 case reports• Only 2 required surgical intervention • No long term sequelae

Severe complications after MMC maintenance Rx• 4 case reports• None required surgery• No long term sequelae

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 failures

Costs 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

Will reach target of 328 patients in a few months• SWOG study, target 340 patients, starting soon

• No plans to license gemcitabine for intravesical use(coming off patent)

New Agents

Apaziquone (EOquin) Spectrum Pharmaceuticals

• Phase II study in 46 patients: 6 instillations produced

67% CR of marker lesion Van der Heijden 2006

• Awaiting £350K funding and EORTC support for 800

patient Phase III study

• 6-8 years from completion

New Approaches

• PDT 5-ALA Berger 2003

• Oral chemopreventionCelecoxib Mohammed 2006

Tegafur (5-FU precursor) Kubota 1999

Verapamil + adriamycin Tsushima 1994

• Chemosensitivity testsIn vitro sensitivity assays Burgues 2005

• Bioadhesive microspheres

Adheres to urothelium

Releases Placitaxel LeVisage 2004

• Microwave Hyperthemia Colombo 2003

New Approaches

•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

New Approaches

‘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

EMDA MMC/ BCG vs BCG:

New Approaches

Problems of ward based intravesical chemotherapy

• Timing - giving drug within 6 hours

• Communication

• Who gives it ?

• Special precautions ≠ Open ward environment

• Monitoring patient

• Releasing drug after 1 hour

• Cytotoxic disposal

Theatre administration

Advantages• Its been given!

• Urologist takes responsibility

• Administered in a controlled environment

• Pts are fasted for 6 hours: concentrates urine

• Known ‘no residual volume’

• Irrigation not required

• Patient asleep/drowsy for most of the hour

• Monitored continuously in recovery

Results

• 16% not suitable: Deep resection

Large resection area

Invasive tumour

Heavy bleeding

• 195 instillations in 170 patients, Historical control group

Median follow-up (months)

Recurrence rate (%)

Theatre MMC 16 37.5

TURBT only 20 55.9

Results

Complications

• 1 Spillage of MMC in recovery

• 1 Abdo pain in recovery MMC released early

• Discomfort same as post-op catheterised pts without MMC

• 12 trusts giving MMC in theatre: No reported adverse events

• Further 16 awaiting protocol clearance

The future

• Chemo-resectionForthcoming EORTC trial

Pts choice: Immediate single dose MMC at Dx versus TURBT

• Antisense oligodeoxynucleotidesCauses chemosensitisation and increases cytotoxic potential of MMC

• Oncolytic retrovirus therapy Hanel 2004

Kausch 2006

Conclusions

• No new drugs in the near future

Improve the effectiveness of what we have

• One immediate post-operative instillationAll patients: single, multi-focal or recurrent

In theatre or within 6 hours, fasting, no residual

• EMDA MMC/BCG for high risk non muscle invasive TCC

• Chemo-resection - will TURBT go the way of TURP?

Level I evidence