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Overview of intravesical therapy: Current Controversies


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Overview of intravesical therapy: Current Controversies

  1. 1. Miss Jo Cresswell Consultant Urologist James Cook University Hospital, Middlesbrough Overview of Intravesical Therapy: Current Controversies
  2. 2. Overview Intravesical, Oct 2010 Intravesical Therapy Single Immediate Instillation Maintenance Chemotherapy BCG Failure T1G3
  3. 3. Single instillation of MMC: Always appropriate? Single instillation of intravesical chemotherapy Intravesical , Oct 2010
  4. 4. <ul><li>“ One immediate post-operative instillation of chemotherapy should be given in all patients after TUR of presumably non-muscle invasive bladder cancer.” </li></ul><ul><li>(EAU Guidelines, 2009, Level 1a evidence) </li></ul><ul><li>↓ risk of recurrence by 50% at 2 years </li></ul><ul><li>OR 39% reduction in recurrence with single instillation </li></ul><ul><li>48.4% versus 36.7%, median FU 3.5 yrs </li></ul><ul><li>(Metanalysis Sylvester et al, J Urol 2004) </li></ul><ul><li>However, 50% of European urologists, and 4% in USA routinely.. </li></ul>Single instillation of intravesical chemotherapy Intravesical, Oct 2010
  5. 5. <ul><li>MMC in UK – timing..... </li></ul><ul><li>Within 24 hours - evidence from literature </li></ul><ul><li>Within 6 hours – recommended by EAU </li></ul><ul><li>Immediate intra-op instillation </li></ul><ul><li>(Mostafid et al, 2006) </li></ul><ul><li>Benefits: </li></ul><ul><li>Tolerability=dwell time </li></ul><ul><li>Immediate </li></ul><ul><li>Shorter hospital stay </li></ul>Single instillation of intravesical chemotherapy NMIBC, May 2010
  6. 6. <ul><li>Single instillation for all new tumours..... </li></ul><ul><li>Appears solid/high grade </li></ul><ul><li>Visual assessment </li></ul><ul><li>85% specific, 90% sensitive </li></ul><ul><li>(Cresswell et al, 2007) </li></ul><ul><li>Pros: </li></ul><ul><li>Why not? </li></ul><ul><li>Potential benefit even if high grade </li></ul><ul><li>Cons: </li></ul><ul><li>Solid tumours </li></ul><ul><li>?MMC unnecessary, more treatment reqd </li></ul><ul><li>Cost of MMC </li></ul><ul><li>Often large tumours, perforation/bleeding more common </li></ul>Single instillation of intravesical chemotherapy NMIBC, May 2010
  7. 7. A prospective study of the accuracy of flexible cystoscopy: <ul><li>Haematuria clinic </li></ul><ul><li>89 new tumours (10 MI, 79 NMIBC) </li></ul><ul><li>Prospective study </li></ul><ul><li>Cystoscopists asked to indicate if NMIBC or muscle-invasive </li></ul><ul><li>Cp to TURBT histology </li></ul><ul><li>Sensitivity 90%,Specificity 85% </li></ul><ul><li>Those incorrectly assessed as MI – T1 </li></ul><ul><li>Prev studies Herr et al, 93% accurate for low grade recurrence </li></ul>NMIBC, May 2010 Prediction of stage and grade
  8. 8. <ul><li>Single instillation for all new tumours..... </li></ul><ul><li>An accepted standard of care </li></ul><ul><li>Surely not controversial ......... </li></ul><ul><li>RCT cp single instillation of epirubicin vs no instillation </li></ul><ul><li>219 patients. ↓Risk of recurrence by 15% </li></ul><ul><li>BUT no benefit for intermediate/high risk tumours </li></ul><ul><li>(Gudjonsson et al, 2009) </li></ul><ul><li>Overall 8.5 pts receive instillations to prevent 1 recurrence </li></ul><ul><li>often small, low risk </li></ul><ul><li>Adds time, expense, side effects for small gain </li></ul><ul><li>(Herr, 2009) </li></ul>NMIBC, May 2010 Single instillation of intravesical chemotherapy
  9. 9. <ul><li>A new EAU recommendation..... </li></ul><ul><li>‘‘ A single instillation of a chemotherapeutic agent after TUR should be administered only in primary, solitary, low-grade NMIBC.” </li></ul><ul><li>(Brausi, 2010) </li></ul><ul><li>Intermediate risk tumours should be given course of maintenance BCG, chemotherapy if not tolerated (and no immediate instillation is required) </li></ul>NMIBC, May 2010 Single instillation of intravesical chemotherapy
  10. 10. <ul><li>Immediate instillation after TURBT for recurrence.... </li></ul><ul><li>Mechanism of action of MMC: </li></ul><ul><li>Destruction of circulating cancer cells </li></ul><ul><li>Prevention of seeding into disrupted urothelium </li></ul><ul><li>Surely this is effective after TURBT for recurrence..... </li></ul><ul><li>(Grey et al, BJMSU, 2009 – small study, no difference) </li></ul><ul><li>(Gudjonsson et al, 2009 -no benefit for recurrent tumours) </li></ul><ul><li>?Intra-operative instillation followed by course of MMC </li></ul>NMIBC, May 2010 Single instillation of intravesical chemotherapy
  11. 11. Re-resection of high-grade disease: a question of quality? <ul><ul><ul><li>Accurate staging/Grading </li></ul></ul></ul><ul><ul><ul><li>Removal of macroscopic disease </li></ul></ul></ul>Re-resection of high grade disease NMIBC, May 2010
  12. 12. <ul><ul><ul><li>Which cases warrant early re-resection? </li></ul></ul></ul><ul><ul><ul><li>T1 -Yes </li></ul></ul></ul><ul><ul><ul><li>Ta - ?? </li></ul></ul></ul><ul><ul><ul><li>Muscle present - ?No </li></ul></ul></ul><ul><li>EAU Guidelines: </li></ul><ul><li>“ A second TUR should be considered when the initial resection was incomplete, or when the pathologist has reported that the specimen contained no muscle tissue. Furthermore, a second TUR should be performed when a high-grade, non-muscle invasive tumour or aT1 tumour has been detected at the initial TUR.” </li></ul>Re-resection of high grade disease NMIBC, May 2010
  13. 13. What is the evidence to support this recommendation? <ul><li>Residual disease on re-resection </li></ul><ul><li>Ta/cis 31%, T1 51.7% </li></ul><ul><li>(Herr et al, 1999) </li></ul><ul><li>Ta 27-72%, T1 33-78% </li></ul><ul><li>(Babjuk, 2009) </li></ul><ul><li>Understaging </li></ul><ul><li>T1: up to 40% upstaged to T2 on cystectomy </li></ul><ul><li>(Dutta et al, 2001) </li></ul><ul><li>TaG3 (5%), T1G3 (30%) </li></ul><ul><li>(Herr et al, 2008) </li></ul>NMIBC, May 2010 Re-resection of high grade disease <ul><li>↓ effectiveness of adjuvant treatment </li></ul><ul><li>Understaging of disease-> inappropriate treatment </li></ul><ul><li>Poorer prognosis </li></ul>
  14. 14. Effect on prognosis <ul><li>RCT cp routine re-resection to initial TUR only in T1 disease </li></ul><ul><li>Progression in 6.5% cp to 23.5% </li></ul><ul><li>(Divrik et al, 2010) </li></ul><ul><li>Can re-resection compensate for initial incomplete resection? </li></ul><ul><li>Progression may be worse even after re-resection </li></ul>Re-resection of high grade disease NMIBC, May 2010
  15. 15. Most important risk factor for understaging was absence of muscle <ul><li>Muscle absent in 30-50% specimens </li></ul><ul><li>M’Boro data </li></ul><ul><li>Muscle present in 45.8-67.3% of G3 </li></ul><ul><li>↑ with seniority of surgeon </li></ul><ul><li>(Jesuraj et al, 2008) </li></ul><ul><li>Understaging: </li></ul><ul><li>If muscle present 30% </li></ul><ul><li>If muscle absent 64% </li></ul><ul><li>( Dutta et al, 2001) </li></ul>Re-resection of high grade disease NMIBC, May 2010 Even if muscle present, high-grade disease warrants re-resection
  16. 16. Decisions for re-resection ? <ul><li>No muscle present – Tx </li></ul><ul><li>TaG3/T1G3 </li></ul><ul><li>Review of path slides, discuss at MDT </li></ul><ul><li>Presence of lymphovascular invasion, micropapillary variants </li></ul><ul><li>Conflicts with imaging </li></ul><ul><li>Patient characteristics </li></ul><ul><li>Young patients, fit for radical treatment </li></ul><ul><li>Older, unfit patients – risk vs benefit </li></ul>Re-resection of high grade disease NMIBC, May 2010
  17. 17. <ul><li>Variation in recurrence rates between institutions </li></ul><ul><li>7.4-45.8% </li></ul><ul><li>(Brausi et al, 2002) </li></ul><ul><li>Persistant disease </li></ul><ul><li>due to variability in quality of TUR </li></ul><ul><li>Presence of detrusor muscle a measure of quality of TUR? </li></ul><ul><li>Very popular concept </li></ul><ul><li>Possible standard for audit/competence? </li></ul>Quality of TURBT NMIBC, May 2010
  18. 18. <ul><ul><li>Presence of detrusor muscle: </li></ul></ul><ul><ul><li>Reduces risk of recurrence </li></ul></ul><ul><ul><li>DM – 21% RR FFC </li></ul></ul><ul><ul><li>No DM – 44.4% </li></ul></ul><ul><ul><li>Even for small, low grade tumours </li></ul></ul><ul><ul><li>(Mariappan et al, 2010) </li></ul></ul><ul><ul><li>Dependent on operator experience </li></ul></ul><ul><ul><li>Junior – 56.8% </li></ul></ul><ul><ul><li>Senior – 72.6% </li></ul></ul><ul><li>Effect of training: </li></ul><ul><li>RR 28% for juniors </li></ul><ul><li>8% for seniors </li></ul><ul><li>With training ↑DM, and ↓Rec </li></ul><ul><li>(Brausi et al, 2008) </li></ul><ul><li>Reasons for inadequate TUR? </li></ul><ul><li>Lack of experience </li></ul><ul><li>Fear of perforation </li></ul><ul><li>Perforation 1.3-3.5% (Nieder et al, 2005) </li></ul><ul><li>On cystography 58.3% (Balbay, 2005) </li></ul>NMIBC, May 2010 Quality of TURBT
  19. 19. <ul><li>What is a successful TURBT? </li></ul><ul><li>No lesions missed (PDD) </li></ul><ul><li>Staging assessed correctly </li></ul><ul><li>Without complications </li></ul><ul><li>“ Larger, high grade lesions should be resected by seniors” </li></ul><ul><li>(Mariappan et al, 2010) </li></ul><ul><li>BUT what of training... </li></ul><ul><li>SpR resects, consultant takes deeper resection separately </li></ul><ul><li>Emphasis on quality of resection </li></ul><ul><li>Re-resection with patient paralysed </li></ul><ul><li>Recent innovations may be making us reflect more carefully on technique </li></ul>Quality of TUR NMIBC, May 2010
  20. 20. <ul><ul><ul><li>BCG Failures </li></ul></ul></ul><ul><ul><ul><li>When has BCG failed? </li></ul></ul></ul><ul><ul><ul><li>What treatment is available? </li></ul></ul></ul>Failure of intravesical treatment NMIBC, May 2010
  21. 21. Definition of failure of BCG: Intolerance – patient intolerant of side-effects BCG resistance- recurrence/persistance of lesser disease, resolves with further BCG BCG Relapsing-recurrence after initial resolution BCG Refractory-not improving or worsening with BCG Failure of intravesical treatment NMIBC, May 2010
  22. 22. <ul><li>“ Treatment with BCG is considered to have failed if high-grade, non-muscle invasive tumour is present at 3 and 6 months” </li></ul><ul><li>(EAU Guidelines) </li></ul><ul><li>Current recommendation : </li></ul><ul><li>Offer radical cystectomy </li></ul><ul><li>BUT is it reasonable or safe to wait for 6 months? </li></ul><ul><li>Patient Factors: </li></ul><ul><li>Patient Choice </li></ul><ul><li>Patient Age </li></ul><ul><li>Patient Fitness </li></ul>NMIBC, 2010 Failure of intravesical treatment Tumour Charactistics: Size Multiplicity Cis Stage T1 vs Ta *Must be sure of staging
  23. 23. <ul><li>Second induction course of BCG can improve response rate (57-80%) </li></ul><ul><li>(Herr et al, 2003) </li></ul><ul><li>What is the risk of progression for high risk NMIBC? </li></ul><ul><li>17% progression at 1 year </li></ul><ul><li>45% progression at 5 years </li></ul><ul><li>Persistant disease at 3/12 check cysto -> poor prognosis </li></ul><ul><li>(Solsona et al, 2000) </li></ul><ul><li>If recurs <1 yr poorer prognosis </li></ul><ul><li>If recurs >1 yr re-challenge with BCG </li></ul><ul><li>(Gallagher et al, 2008) </li></ul>NMIBC, May 2010 Failure of intravesical treatment
  24. 24. <ul><li>When to offer radical cystectomy? </li></ul><ul><li>As primary therapy, but morbidity favours BCG initially </li></ul><ul><li>If worsening of disease at 3/12 CC, progression </li></ul><ul><li>Dysfunctional bladder </li></ul><ul><li>Impossible to control disease cystoscopically </li></ul><ul><li>Failure of second induction course </li></ul><ul><li>In other cases discuss with patient... </li></ul><ul><li>From the outset – “50:50 chance of surviving with bladder to 5 years” </li></ul>Failure of intravesical treatment NMIBC, May 2010
  25. 25. <ul><li>What if the patient is unfit/unwilling..... </li></ul><ul><li>Currently offer 2 nd course of BCG, endoscopic management </li></ul><ul><li>Other options: </li></ul><ul><li>Device assisted – Thermotherapy, EMDA </li></ul><ul><li>Chemotherapy – Gemcitabine, Docetaxol </li></ul><ul><li>Immunotherapy – IFN α </li></ul>Failure of intravesical treatment NMIBC, May 2010
  26. 26. Thermotherapy: <ul><li>Synergo system </li></ul><ul><li>Bladder heated to approx 42ºC </li></ul><ul><li>MMC circulated into bladder for 2 x 30 minute treatments </li></ul><ul><li>Initial 6 weekly treatments </li></ul><ul><li>Maintenance single treatment at 4-6 week intervals </li></ul><ul><li>HYMN trial due to open </li></ul><ul><li>TC cp to standard of care </li></ul><ul><li>BCG failure, high grade </li></ul>Failure of intravesical treatment NMIBC, May 2010
  27. 27. Results of thermotherapy: <ul><li>Retrospective study showed 56% DFS at 2 years for BCG refractory (111 pts) </li></ul><ul><li>a) High vs int risk </li></ul><ul><li>b) 6x vs Maintenance </li></ul><ul><li>(Nativ et al, 2009) </li></ul><ul><li>European Synergo group </li></ul><ul><li>34 BCG refractory cis </li></ul><ul><li>approx 50% DFS at 2 yrs, 92% at 1year </li></ul><ul><li>(Witjes et al, 2009) </li></ul>Failure of intravesical treatment NMIBC, May 2010 a) b)
  28. 28. Other options: <ul><li>EMDA MMC vs BCG in high risk (not BCG failures) </li></ul><ul><li>Equivalent recurrence rates </li></ul><ul><li>at 6/12 – 58 vs 64% </li></ul><ul><li>(Di Stasi et al, 2003) </li></ul><ul><li>Immunotherapy: </li></ul><ul><li>BCG failures – BCG + IFN </li></ul><ul><li>45% DFS at 2 yrs </li></ul><ul><li>(Joudi et al, 2006) </li></ul><ul><li>Intravesical Gemcitabine </li></ul><ul><li>BCG failures </li></ul><ul><li>1yr DFS – 21% </li></ul><ul><li>(Dalbagni et al, 2006) </li></ul><ul><li>Overall, results are variable and given 80-90% cure with RC, ?only acceptable if unfit/unwilling </li></ul><ul><li>Effects of thermotherapy/EMDA on bladder symptoms ↑ ..... </li></ul><ul><li>Long-term bladder symptoms? </li></ul>Failure of intravesical treatment NMIBC, May 2010
  29. 29. Thank you!