Latest Developments in Intravesical Therapy

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A part of the Virtual Edition on Intravesical Therapy on www.bjui.org. Visit the site to read the full article.

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Latest Developments in Intravesical Therapy

  1. 1. Hugh Mostafid Consultant Urologist North Hampshire Hospital Basingstoke Latest Developments in Intravesical Therapy
  2. 2. Intravesical therapy in 2011 <ul><li>Trends </li></ul><ul><li>Treatment based on risk groups </li></ul><ul><li>Focus on intermediate group </li></ul><ul><li>Maintenance intravesical chemotherapy </li></ul><ul><li>Reduction of side-effects </li></ul><ul><li>Device assisted therapy </li></ul><ul><li>BCG failures </li></ul><ul><li>New agents/concepts </li></ul>
  3. 3. Intravesical therapy in 2011 <ul><li>Trends </li></ul><ul><li>Treatment based on risk groups </li></ul><ul><li>Focus on intermediate group </li></ul><ul><li>Maintenance intravesical chemotherapy </li></ul><ul><li>Reduction of side-effects </li></ul><ul><li>Device assisted therapy </li></ul><ul><li>BCG failures </li></ul><ul><li>New agents/concepts </li></ul>
  4. 4. Treatment based on risk groups <ul><li>Limitations </li></ul><ul><li>Predates BCG maintenance </li></ul><ul><li>No re-TURBT </li></ul><ul><li>20% had no intravesical therapy </li></ul><ul><li><10% received immediate instillation </li></ul>EORTC risk tables Sylvester 2006 1-17 <1-5 46-62 24-38 35 Intermediate Risk Progression Recurrence % of total 6-45 1-17 46-78 24-61 15 High Risk 1-6 <1 31-46 15-24 50 Low Risk 5yr 1yr 5 yr 1 yr
  5. 5. Intravesical therapy in 2011 <ul><li>Trends </li></ul><ul><li>Treatment based on risk groups </li></ul><ul><li>Focus on intermediate group </li></ul><ul><li>Reduction of side-effects </li></ul><ul><li>Maintenance intravesical chemotherapy </li></ul><ul><li>Device assisted therapy </li></ul><ul><li>BCG failures </li></ul><ul><li>New agents/concepts </li></ul>
  6. 6. Intermediate risk group Ta-T1,G1-2 Multifocal >3cm diameter <ul><li> Recurrence rate </li></ul><ul><li>Progression rate ? </li></ul>1-17 <1-5 46-62 24-38 35 Intermediate Risk Progression Recurrence % of total 6-45 1-17 46-78 24-61 15 High Risk 1-6 <1 31-46 15-24 50 Low Risk 5yr 1yr 5 yr 1 yr
  7. 7. Intermediate risk group <ul><li>Why the interest in the intermediate group? </li></ul><ul><li>Single instillation is suboptimal </li></ul><ul><li>Chemo or BCG? </li></ul><ul><li>If chemo, optimal schedule unknown </li></ul><ul><li>X6 or maintenance (how long?) </li></ul><ul><li>If BCG, how to reduce side-effects </li></ul><ul><li>How long maintenance? </li></ul>
  8. 8. Intravesical therapy in 2011 <ul><li>Trends </li></ul><ul><li>Treatment based on risk groups </li></ul><ul><li>Focus on intermediate group </li></ul><ul><li>Maintenance intravesical chemotherapy </li></ul><ul><li>Reduction of side-effects </li></ul><ul><li>Device assisted therapy </li></ul><ul><li>BCG failures </li></ul><ul><li>New agents/concepts </li></ul>
  9. 9. Long term maintenance chemotherapy in Intermediate risk group <ul><li>Long term chemotherapy maintenance Friedrich 2007 </li></ul><ul><li>495 pts </li></ul><ul><li>BCGx6 vs. MMCx6 vs. MMC 3yrs </li></ul><ul><li>MMC 3yrs reduced 3yr RR to 14% </li></ul><ul><li>Toxicity acceptable </li></ul><ul><li>But </li></ul><ul><li>Only 20mg MMC used </li></ul><ul><li>No immediate single dose </li></ul><ul><li>Only 8% finished maintenance </li></ul><ul><li>No data on progression </li></ul><ul><li>But short term intensive Rx over < 1 yr may provide as good results as long term chemo </li></ul><ul><li>Tolley 1996,Schwaibold 1997, Koga 2004, Kuroda 2004 </li></ul><ul><li>Confounding effect of whether or not one immediate dose was given Bouffioux 1995, Ali-el-Dein 1997 </li></ul><ul><li>Carcinogenic effect of long-term chemoRx </li></ul>
  10. 10. Intravesical therapy in 2011 <ul><li>Trends </li></ul><ul><li>Treatment based on risk groups </li></ul><ul><li>Focus on intermediate group </li></ul><ul><li>Maintenance intravesical chemotherapy </li></ul><ul><li>Reduction of side-effects </li></ul><ul><li>Device assisted therapy </li></ul><ul><li>BCG failures </li></ul><ul><li>New agents/concepts </li></ul>
  11. 11. BCG maintenance <ul><li>Optimal therapy for reducing progression rate Sylvester 2002 </li></ul><ul><li>But </li></ul><ul><li>5% stop during induction </li></ul><ul><li>20% stop during maintenance </li></ul><ul><li> Reduced toxicity desirable </li></ul>
  12. 12. BCG Toxicity Spanish CUETO group 53 61 69 Median followup 430 155 500 N 1/3 and 1/6 dose have same toxicity 1/3 dose toxicity lower 1/3 dose toxicity lower Toxicity 1/3 dose is minimum effective dose for int risk 27mg vs. 13.5.mg vs. 30 mg MMC intermediate risk 95.011 2007 1/3 dose as effective as full dose for high risk disease 81mg vs. 27mg in high risk tumours 95.012 2005 No diff in rec. or prog except for multifocal tumours. Trend towards lower RR with full dose in high risk tumours 81mg vs. 27mg BCG Connaught 90.008 2002 Oncological outcome Groups
  13. 13. Low Dose BCG vs. MMC <ul><li>CUETO 95011 Ojea 2007 </li></ul><ul><li>Significantly longer DFI for BCG 27mg versus MMC 30 mg </li></ul><ul><li>No significant difference in progression rate or cancer specific survival </li></ul><ul><li>Local and systemic toxicity higher for both BCG groups </li></ul><ul><li>BUT </li></ul><ul><li>Only 30mg MMC used 12 Instillations over 18 weeks </li></ul><ul><li>No immediate single dose of chemo </li></ul>
  14. 14. BCG Toxicity <ul><li>EORTC 30962 </li></ul><ul><li>1/3 vs. full dose </li></ul><ul><li>1 year vs. 3 years maintenance </li></ul><ul><li>1355 patients recruited, closed in 2005 </li></ul><ul><li>Last patients finish 3 yrs maintenance in 3/08 </li></ul><ul><li>First report, on toxicity data expected in late 2008 </li></ul>
  15. 15. EORTC <ul><li>EORTC 30911 </li></ul><ul><li>3 yrs maintenance Epirubicin vs. BCG Sylvester 2001 </li></ul><ul><li>Long term results to be presented at EAU 2008 </li></ul>
  16. 16. Reducing BCG side-effects <ul><li>Reducing the number of instillations of BCG maintenance vs. reducing the dose </li></ul><ul><li>Proposed EORTC phase II study </li></ul>
  17. 17. Intravesical therapy in 2011 <ul><li>Trends </li></ul><ul><li>Treatment based on risk groups </li></ul><ul><li>Focus on intermediate group Maintenance intravesical chemotherapy </li></ul><ul><li>Reduction of side-effects </li></ul><ul><li>Device assisted therapy </li></ul><ul><li>BCG failures </li></ul><ul><li>New agents/concepts </li></ul>
  18. 18. High Risk group G3T1 Multifocal >3 recurrences in 24 months CIS  progression  side-effects acceptable 1-17 <1-5 46-62 24-38 35 Intermediate Risk Progression Recurrence % of total 6-45 1-17 46-78 24-61 15 High Risk 1-6 <1 31-46 15-24 50 Low Risk 5yr 1yr 5 yr 1 yr
  19. 19. Device assisted therapy <ul><li>E lectro M otive D rug A dministration </li></ul>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
  20. 20. EMDA MMC/BCG vs BCG <ul><li>‘ 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.’ </li></ul><ul><li> DiStasi 2006 </li></ul>10.6 p=0.01 10.9 p=0.045 12.6 p=0.004 16 p=0.0012 48 p=0.0012 Difference 16.2 32.4 21.9 57.9 21 BCG 5.6 21.5 9.3 41.9 69 EMDA MMC + BCG Disease-specific mortality % Overall mortality % Progression % Recurrence % Disease free interval (months)
  21. 21. Intravesical therapy in 2011 <ul><li>Trends </li></ul><ul><li>Treatment based on risk groups </li></ul><ul><li>Focus on intermediate group </li></ul><ul><li>Maintenance intravesical chemotherapy </li></ul><ul><li>Reduction of side-effects </li></ul><ul><li>Device assisted therapy </li></ul><ul><li>BCG failures </li></ul><ul><li>New agents/concepts </li></ul>
  22. 22. Thermochemotherapy <ul><li>Effective as prophylaxis and ablative Rx for G3 tumours </li></ul><ul><li>Effective in BCG failures: </li></ul><ul><li>90 pts inc. 41 BCG failures </li></ul><ul><li>1 yr RR: 14% 23% </li></ul><ul><li>2 yr RR: 25% 41% </li></ul><ul><li>No progression </li></ul><ul><li>CIS: 57 pts inc 40 BCG failures: 94% initial CR, 30% 1yr RR </li></ul><ul><li>Phase III study recruiting: TCT vs. BCG in high risk NMIBC </li></ul>Gofrit 2004 Van der Heijden 2004 Witjes EAU 2007
  23. 23. TCT vs EMDA vs MMC vs BCG <ul><li>Neo-adjuvant Rx of a single recurrent tumour </li></ul><ul><li>CR </li></ul><ul><li>TCT 66% </li></ul><ul><li>EMDA MMC 40% </li></ul><ul><li>MMC 28% </li></ul><ul><li> Colombo 2001 </li></ul><ul><li>High risk NMIBC </li></ul><ul><li> </li></ul><ul><li> 6 mo.CR </li></ul><ul><li>MMC 31% </li></ul><ul><li>EMDA MMC 58% </li></ul><ul><li>BCG 64% </li></ul><ul><li> </li></ul>Di Stasi 2003
  24. 24. Intravesical therapy in 2011 <ul><li>Trends </li></ul><ul><li>Treatment based on risk groups </li></ul><ul><li>Focus on intermediate group </li></ul><ul><li>Maintenance intravesical chemotherapy </li></ul><ul><li>Reduction of side-effects </li></ul><ul><li>Device assisted therapy </li></ul><ul><li>BCG failures </li></ul><ul><li>New agents/concepts </li></ul>
  25. 25. BCG failures <ul><li>BCG combined with Interferon-  O’Donnell 2004 Joudi 2006 </li></ul><ul><li>467 BCG intolerant or failures received  dose BCG+IFN-  </li></ul><ul><li>536 BCG naive pts received standard BCG+IFN-  </li></ul><ul><li>45% of BCG failures remained disease free at median follow-up of 24-months </li></ul><ul><li>4% progressed to T2 </li></ul>
  26. 26. Intravesical therapy in 2011 <ul><li>Trends </li></ul><ul><li>Treatment based on risk groups </li></ul><ul><li>Focus on intermediate group </li></ul><ul><li>Maintenance intravesical chemotherapy </li></ul><ul><li>Reduction of side-effects </li></ul><ul><li>Device assisted therapy </li></ul><ul><li>BCG failures </li></ul><ul><li>New agents/concepts </li></ul>
  27. 27. New Agents - Phase I studies <ul><li>Pirirubicin Okamura 2002 </li></ul><ul><li>Valrubicin Steinberg 2000 </li></ul><ul><li>Vinorelbine Bonfil 2001 </li></ul><ul><li>Meglumine  -linolenic acid Harris 2002 </li></ul><ul><li>Recombinant human interleukin-12 Weiss 2003 </li></ul><ul><li>Suramin Ord 2005 </li></ul><ul><li>Docetaxel McKiernan 2006 </li></ul><ul><li>Ethics of phase II studies in high risk BCG failures </li></ul><ul><li>Costs of phase III studies </li></ul>
  28. 28. New Agents <ul><li>Gemcitabine Lilly Pharmaceuticals </li></ul><ul><li>Phase II marker lesion studies </li></ul><ul><li>6 weeks instillations: 56% CR Gontero 2004 </li></ul><ul><li>In total 6 phase II studies, total of 184 pts, CR 44-66% </li></ul><ul><li>Phase III studies </li></ul><ul><li>German co-operative group, immediate post-op gemcitabine </li></ul><ul><li>Results awaited </li></ul><ul><li>SWOG study, target 340 patients, starting soon </li></ul><ul><li>No plans to license gemcitabine for intravesical use </li></ul><ul><li>(coming off patent) </li></ul>
  29. 29. New Agents <ul><li>Apaziquone (Eoquin, EO9) Spectrum Pharmaceuticals </li></ul><ul><li>Indolequininone derivative of MMC </li></ul><ul><li>Both Eoquin and MMC require activation by cellular reductase enzymes </li></ul><ul><li>Phase II study in 46 patients: 6 instillations produced 67% CR of marker lesion </li></ul><ul><li>Currently: </li></ul><ul><li>RCT of 1 immediate dose Eoquin vs. nothing (U.S) </li></ul><ul><li>Adjuvant Eoquin for pts with high risk BCG refractory NMIBC </li></ul>Van der Heijden 2006
  30. 30. New Agents <ul><li>Urocidin  (MCC) Bioniche Life Sciences </li></ul><ul><li>A formulation of Mycobacterial Cell Wall-DNA Complex (MCC) </li></ul><ul><li>2 Phase III trials underway: (U.S) </li></ul><ul><li>- 2nd line therapy in BCG failures </li></ul><ul><li>- Urocidin vs. BCG as first-line therapy in NMIBC </li></ul>
  31. 31. New Agents <ul><li>Keyhole limpet hemocyanin (KLH) </li></ul><ul><li>A high-molecular-weight protein antigen collected from the haemolymph of the sea mollusk Megathura crenulata </li></ul><ul><li>Powerful non-specific immune response modifier </li></ul><ul><li>Small number of long term remissions in CIS Jurincic-Winkler 2000 </li></ul><ul><li>Study of KLH vs. MMC just finishing (P.I. : Prof Witjes) </li></ul>
  32. 32. New concepts <ul><li>Photodynamic therapy Bader EAU 2007 </li></ul><ul><li>H-ALA (Hexvix)  Protoporphyrin IX (PPIX) intracellularly </li></ul><ul><li>PPIX is a photosensitiser </li></ul><ul><li>14 pts with High grade NMIBC </li></ul><ul><li>3 PDT sessions using a high power white light source </li></ul><ul><li>Technically feasible and safe </li></ul>
  33. 33. Low Risk group Single TaG1, <3cm  Recurrence rate  Side effects not justified 1-17 <1-5 46-62 24-38 35 Intermediate Risk Progression Recurrence % of total 6-45 1-17 46-78 24-61 15 High Risk 1-6 <1 31-46 15-24 50 Low Risk 5yr 1yr 5 yr 1 yr
  34. 34. New concepts: Low risk group <ul><li>Single immediate instillation following TURBT is sufficient treatment Sylvester 2006 </li></ul><ul><li>Watchful waiting at recurrence is safe </li></ul><ul><li>Soloway 2003, Gofrit 2006, Miller 2007 </li></ul><ul><li>PBR tariff for cystodiathermy - TURBT: £730 - £1502 </li></ul><ul><li> Chemoresection? </li></ul>
  35. 35. Conclusions <ul><li>Superficial  NMIBC  Risk groups </li></ul><ul><li>Optimal Rx for intermediate risk group? </li></ul><ul><li>Reduce toxicity of BCG </li></ul><ul><li>Optimal Rx for BCG failures </li></ul><ul><li>Development of new compounds/DAT/concepts </li></ul>

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