1. Radiotherapy for bladder cancer Nicholas James School of Cancer Sciences University of Birmingham

2. Treatment approaches – muscle invasive disease Neoadjuvant chemotherapy RT Cystectomy RT Cystectomy Adjuvant chemotherapy in selected cases Chemotherapy on relapse Salvage cystectomy

3. Patterns of care vary worldwide UK RT: cystectomy 3:1 Munro N et al. Int J RadiatOncolBiol Phys. 2010 Sweden RT: cystectomy 1:4 Jahnson S et al. Scand J UrolNephrol. 2009 USA Surgery widely available RT availability varies by age, sex and address Overall round 11% receive RT (SEER) Konety BR et al. J Urol. 2003

4. Some misconceptions about non-surgical therapy for bladder cancer Survival is better after surgery Radiotherapy results in a small shrunken bladder and poor quality of life By giving RT urologists pass control of the patients to the oncologists

5. Multidisciplinary working Initial flexible cystoscopy Urology input Rigid cystoscopy and TURBT Urology input Neoadjuvant chemotherapy Urology input Urology input RT +/- chemotherapy Urology input Post RT surveillance Salvage cystectomy ( around 20%)

6. Survival after surgery 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

7. Survival surgeryvs radiotherapy Stein et al: 1054 cystectomy patients 5- and 10-YS 60% and 43% Rödel et al: 415 RT patients 5- and 10-YS 51% and 31% However, cystectomy series: included 213 T0, Ta, Tis patients excluded 112 inoperable patients If comparison is restrictedto operable muscle-invasive disease, 5-YS: radical cystectomy 47% Conservative therapy 45% Rödel C, et al: J Clin Oncol 20: 3061-3071, 2002 Stein JP et al JCO Feb 1 2001: 666-675

8. Conclusion: surgery vs. RT Patterns of care very variable Long term survival rates comparable with surgery or RT No compelling evidence for superiority of surgery

9. Is surgery better than radiotherapy for bladder cancer? It doesn’t matter

10. Patients unsuitable for surgery Elderly Severe cardiovascular or chest problems Obese Diabetes Patients reluctant or unable to cope with stoma etc

11. Age at diagnosis Median age in BC2001 and BCON Median age in Skinner series Median age in BA06 & SWOG 8710

12. Can we select good responders? Biological markers Select patients for radiotherapy on basis of initial response to therapy Rationale for Boston approach

13. Boston approach – Trimodality therapy

14. Results – Boston approach 190 patients 124 (65%) retained bladder 41 (22%) Immediate cystectomy 25 (13%) delayed cystectomy Kaufman et al. Proc ASCO 2001 Abstract 683

15. Can we improve local control rates? Neoadjuvant therapy Synchronous therapy Adjuvant therapy

16. MRC Trial - Metastasis Free Survival Lancet. 1999

17. MRC Trial - Loco-regional control Lancet. 1999

18. Synchronous Chemo-radiotherapy Numerous phase I/II studies showing feasibility and safety Three phase III studies RT vs RT + Cisplatinum (NCIC) RT vs RT + nicotinamide/carbogen (BCON) RT vs RT + 5FU/MMC (BC2001)

20. BCON: Aim and endpoints To determine if the hypoxia-modifiers carbogen and nicotinamide increase the efficacy of RT in TCC Primary endpoint cystoscopiccontrol Secondary endpoints: overall survival (OS), local relapse-free survival (RFS), urinary and rectal morbidity

21. RT+ CON RT alone BCON – urinary and bowel toxicity > grade 2

22. Carbogen + Nicotinamide HR 0.86 (0.74-1.0) p=0.06 at 3 years Control arm BCON Primary endpoint – Local control

23. Carbogen + Nicotinamide Control arm BCON Overall survival HR 0.85 (0.73-0.99) p=0.04 at 3 years

24. CT NoCT sRT RHDV RT BC2001: Trial design Patients with muscle invasive bladder cancer RANDOMISE Reduced high dose volume RT + synchronous chemotherapy Standard volume RT† + synchronous chemotherapy Reduced high dose volume RT† Standard volume RT† Pragmatic design: Centres could offer double or either single randomisation Patients ineligible for one randomisation could participate in other

25. Chemotherapy regimen MMC 12mg/m2 5FU 500mg/m2/d RT 55 Gy/20 f or 64 Gy/32 f Weeks 0 1 2 3 4 5 6 7 Target volume tumour + bladder + 1.5-2cm Chemotherapy via peripherally inserted central line as outpatient therapy

26. BC2001 Endpoints Primary: Loco-regional (pelvic) disease free survival Secondary: Overall survival Late toxicity at 1 and 2 years Bladder capacity Quality of Life Acute toxicity Cystoscopic local control at 3 mo, 1 y & 2y Salvage cystectomy rates

27. Patient demographics Performance status Age at randomisation Mean (SD) 70.5 (8.2) years Median (IQR) 71.9 (64.1 - 76.2) years Older than patients in previously published trials including SWOG 87101(median 63 y) and BA062 (median 64 y) Male = 289/360 (80%) Grossman et al NEJM 2003 Volume 349:859-866 Lancet 1999; 354: 533-40

28. Acute toxicity Proportions with a grade 3/4 at any time on treatment: 62/179 (34.6%) CT vs. 49/172 (28.5%) No CT (% of pts with data) Stratified Chi-square test p=0.19 Worst grade of on-treatment toxicity by week

30. Invasive loco-regional disease free survival in chemotherapy comparison 2-yr ILRDFS CT=28/182 82% (95% CI: 75%, 88%) 68% (95% CI: 59%, 75%) No CT=51/178 HR = 0.53 (95% CI: 0.33, 0.84); p=0.007

31. LRDFS - consistency across subgroups Hazard ratio (95% CI) N P-value Randomised sRT 63 0.63 Randomised RHDV 58 Elect sRT 239 RT dose 55Gy/20F 140 0.73 RT dose 64Gy/32F 212 Neoadjuvant CT 118 0.60 No neoadjuvant CT 242 Primary analysis 360

32. OS in chemotherapy randomisation 2-yr OS 62% (95% CI: 54%, 68%) CT = 85/182 60% (95% CI: 52%, 67%) No CT = 98/178 HR = 0.82 (95% CI: 0.61, 1.10); p=0.16

33. Conclusions Bladder preserving therapy gives good long term bladder function Neoadjuvant chemotherapy improves overall survival but probably has little effect on local control Radio-sensitising agents substantially improve local control Time to re-evaluate the role of bladder preservation?