ECCLU 2011 - N. James - Localised invasive bladder cancer - Radiotherapy

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ECCLU 2011 - N. James - Localised invasive bladder cancer - Radiotherapy

  1. 1. Radiotherapy for bladder cancer<br />Nicholas James<br />School of Cancer Sciences<br />University of Birmingham<br />
  2. 2. Treatment approaches – muscle invasive disease<br />Neoadjuvant chemotherapy<br />RT<br />Cystectomy<br />RT<br />Cystectomy<br />Adjuvant chemotherapy in selected cases<br />Chemotherapy on relapse<br />Salvage cystectomy<br />
  3. 3. Patterns of care vary worldwide<br />UK RT: cystectomy 3:1 <br /> Munro N et al. Int J RadiatOncolBiol Phys. 2010<br />Sweden RT: cystectomy 1:4<br />Jahnson S et al. Scand J UrolNephrol. 2009<br />USA <br />Surgery widely available<br />RT availability varies by age, sex and address<br />Overall round 11% receive RT (SEER)<br />Konety BR et al. J Urol. 2003<br />
  4. 4. Some misconceptions about non-surgical therapy for bladder cancer<br />Survival is better after surgery<br />Radiotherapy results in a small shrunken bladder and poor quality of life<br />By giving RT urologists pass control of the patients to the oncologists<br />
  5. 5. Multidisciplinary working<br />Initial flexible cystoscopy<br />Urology input<br />Rigid cystoscopy and TURBT<br />Urology input<br />Neoadjuvant chemotherapy<br />Urology input<br />Urology input<br />RT +/- chemotherapy<br />Urology input<br />Post RT surveillance<br />Salvage cystectomy ( around 20%)<br />
  6. 6. Survival after surgery <br />SWOG 8710 (INT-0080): Randomized Phase III Trial of Neoadjuvant MVAC + Cystectomy Versus Cystectomy Alone in Patients with Locally Advanced Bladder Cancer. Grossman et al NEJM 2003 Volume 349:859-866 <br />
  7. 7. Survival surgeryvs radiotherapy<br />Stein et al: 1054 cystectomy patients 5- and 10-YS 60% and 43%<br />Rödel et al: 415 RT patients 5- and 10-YS 51% and 31% <br />However, cystectomy series:<br />included 213 T0, Ta, Tis patients<br />excluded 112 inoperable patients <br />If comparison is restrictedto operable muscle-invasive disease, 5-YS: <br />radical cystectomy 47%<br />Conservative therapy 45%<br />Rödel C, et al: J Clin Oncol 20: 3061-3071, 2002 <br />Stein JP et al JCO Feb 1 2001: 666-675<br />
  8. 8. Conclusion: surgery vs. RT<br />Patterns of care very variable<br />Long term survival rates comparable with surgery or RT<br />No compelling evidence for superiority of surgery<br />
  9. 9. Is surgery better than radiotherapy for bladder cancer?<br />It doesn’t matter<br />
  10. 10. Patients unsuitable for surgery<br />Elderly<br />Severe cardiovascular or chest problems<br />Obese<br />Diabetes<br />Patients reluctant or unable to cope with stoma<br />etc<br />
  11. 11. Age at diagnosis<br />Median age in <br />BC2001 and BCON<br />Median age in <br />Skinner series<br />Median age in <br />BA06 & SWOG 8710<br />
  12. 12. Can we select good responders?<br />Biological markers<br />Select patients for radiotherapy on basis of initial response to therapy<br />Rationale for Boston approach<br />
  13. 13. Boston approach – Trimodality therapy<br />
  14. 14. Results – Boston approach<br />190 patients<br />124 (65%) retained bladder<br />41 (22%) Immediate cystectomy<br />25 (13%) delayed cystectomy<br />Kaufman et al. Proc ASCO 2001 Abstract 683<br />
  15. 15. Can we improve local control rates?<br />Neoadjuvant therapy<br />Synchronous therapy<br />Adjuvant therapy<br />
  16. 16. MRC Trial - Metastasis Free Survival<br />Lancet. 1999<br />
  17. 17. MRC Trial - Loco-regional control<br />Lancet. 1999<br />
  18. 18. Synchronous Chemo-radiotherapy<br />Numerous phase I/II studies showing feasibility and safety<br />Three phase III studies<br />RT vs RT + Cisplatinum (NCIC)<br />RT vs RT + nicotinamide/carbogen (BCON)<br />RT vs RT + 5FU/MMC (BC2001)<br />
  19. 19. Cisplatinum and RT +/- surgery<br /><ul><li>Coppin et al, J. Clin Onc. 14:2901-2907</li></li></ul><li><ul><li>Coppin et al, J. Clin Onc. 14:2901-2907</li></ul>Cisplatinum and RT +/- surgery<br />
  20. 20. BCON: Aim and endpoints<br />To determine if the hypoxia-modifiers carbogen and nicotinamide increase the efficacy of RT in TCC<br />Primary endpoint cystoscopiccontrol<br />Secondary endpoints: overall survival (OS), local relapse-free survival (RFS), urinary and rectal morbidity<br />
  21. 21. RT+ CON<br />RT alone<br />BCON – urinary and bowel toxicity > grade 2<br />
  22. 22. Carbogen + Nicotinamide<br />HR 0.86 (0.74-1.0) p=0.06 at 3 years<br />Control arm<br />BCON Primary endpoint – Local control<br />
  23. 23. Carbogen + Nicotinamide<br />Control arm<br />BCON Overall survival<br />HR 0.85 (0.73-0.99) p=0.04 at 3 years<br />
  24. 24. CT<br />NoCT<br />sRT<br />RHDV RT <br />BC2001: Trial design<br />Patients with muscle invasive bladder cancer<br />RANDOMISE<br />Reduced high<br />dose volume RT<br />+ synchronous chemotherapy<br />Standard volume RT† <br /> + synchronous chemotherapy<br />Reduced high<br />dose volume RT†<br />Standard volume RT†<br />Pragmatic design: Centres could offer double or either single randomisation <br /> Patients ineligible for one randomisation could participate in other<br />
  25. 25. Chemotherapy regimen<br />MMC 12mg/m2<br />5FU 500mg/m2/d<br />RT 55 Gy/20 f or <br /> 64 Gy/32 f<br />Weeks<br />0 1 2 3 4 5 6 7 <br />Target volume tumour + bladder + 1.5-2cm<br />Chemotherapy via peripherally inserted central <br />line as outpatient therapy <br />
  26. 26. BC2001 Endpoints<br />Primary: <br />Loco-regional (pelvic) disease free survival<br />Secondary: <br />Overall survival <br />Late toxicity at 1 and 2 years <br />Bladder capacity<br />Quality of Life <br />Acute toxicity <br />Cystoscopic local control at 3 mo, 1 y & 2y <br />Salvage cystectomy rates<br />
  27. 27. Patient demographics<br />Performance status<br />Age at randomisation<br />Mean (SD) 70.5 (8.2) years<br />Median (IQR) 71.9 (64.1 - 76.2) years<br />Older than patients in previously published trials including SWOG 87101(median 63 y) and BA062 (median 64 y)<br />Male = 289/360 (80%)<br />Grossman et al NEJM 2003 Volume 349:859-866 <br /> Lancet 1999; 354: 533-40 <br />
  28. 28. Acute toxicity<br />Proportions with a grade 3/4 at any time on treatment:<br /> 62/179 (34.6%) CT vs. 49/172 (28.5%) No CT (% of pts with data) <br />Stratified Chi-square test p=0.19<br />Worst grade of on-treatment toxicity by week<br />
  29. 29. CT<br />No CT<br />P-value*<br />RTOG<br />N=121<br />N=107<br />Overall<br />10 (8.3%)<br />17 (15.9%)<br />0.07<br />GI symptoms<br />1 (0.8%)<br />5 (4.7%)<br />0.07<br />GU symptoms<br />9 (7.4%)<br />12 (11.2%)<br />0.30<br />LENT/SOM<br />N=117<br />N=99<br />Overall<br />61 (52.1%)<br />49 (49.5%)<br />0.77<br />Excl. sexual dysfunction<br />33 (28.2%)<br />27 (27.3%)<br />0.78<br />Late toxicity<br />Proportion of patients with a grade 3/4 toxicity at any time during follow-up (6 months onwards), up to 3 months before a recurrence:<br />*Stratified Chi-square test<br /><ul><li>Patients with no available assessment are excluded from table</li></li></ul><li>Loco-regional disease free survival in chemotherapy randomisation<br /> 2-yr LRDFS <br />67% (95% CI: 58%, 74%)<br />CT=53/182<br />54% (95% CI: 46%, 62%)<br />No CT=74/178<br />HR = 0.67 (95% CI: 0.47, 0.95); p=0.03 <br />
  30. 30. Invasive loco-regional disease free survival in chemotherapy comparison<br /> 2-yr ILRDFS <br />CT=28/182<br />82% (95% CI: 75%, 88%)<br />68% (95% CI: 59%, 75%)<br />No CT=51/178<br />HR = 0.53 (95% CI: 0.33, 0.84); p=0.007 <br />
  31. 31. LRDFS - consistency across subgroups<br />Hazard ratio (95% CI)<br />N P-value<br />Randomised sRT 63 0.63<br />Randomised RHDV 58<br />Elect sRT 239<br />RT dose 55Gy/20F 140 0.73<br />RT dose 64Gy/32F 212<br />Neoadjuvant CT 118 0.60<br />No neoadjuvant CT 242<br />Primary analysis 360<br />
  32. 32. OS in chemotherapy randomisation<br /> 2-yr OS <br />62% (95% CI: 54%, 68%)<br />CT = 85/182<br />60% (95% CI: 52%, 67%)<br />No CT = 98/178<br />HR = 0.82 (95% CI: 0.61, 1.10); p=0.16 <br />
  33. 33. Conclusions <br />Bladder preserving therapy gives good long term bladder function<br />Neoadjuvant chemotherapy improves overall survival but probably has little effect on local control<br />Radio-sensitising agents substantially improve local control<br />Time to re-evaluate the role of bladder preservation?<br />

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