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