This document discusses treatment approaches for bladder cancer including radiotherapy and cystectomy. It summarizes results from several studies comparing outcomes of radiotherapy versus cystectomy, and studies combining radiotherapy with chemotherapy. The key findings are: 1) Long-term survival rates after radiotherapy or cystectomy are comparable. 2) A study found neoadjuvant chemotherapy prior to radiotherapy improved 2-year loco-regional disease-free survival compared to radiotherapy alone. 3) Bladder preserving therapy can provide good long-term bladder function for patients who are not candidates for cystectomy.

1. Radiotherapy for bladder cancerNicholas JamesSchool of Cancer SciencesUniversity of Birmingham

2. Treatment approaches – muscle invasive diseaseNeoadjuvant chemotherapyRTCystectomyRTCystectomyAdjuvant chemotherapy in selected casesChemotherapy on relapseSalvage cystectomy

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

4. Some misconceptions about non-surgical therapy for bladder cancerSurvival is better after surgeryRadiotherapy results in a small shrunken bladder and poor quality of lifeBy giving RT urologists pass control of the patients to the oncologists

5. Multidisciplinary workingInitial flexible cystoscopyUrology inputRigid cystoscopy and TURBTUrology inputNeoadjuvant chemotherapyUrology inputUrology inputRT +/- chemotherapyUrology inputPost RT surveillanceSalvage 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 radiotherapyStein 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 patientsexcluded 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. RTPatterns of care very variableLong term survival rates comparable with surgery or RTNo compelling evidence for superiority of surgery

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

10. Patients unsuitable for surgeryElderlySevere cardiovascular or chest problemsObeseDiabetesPatients reluctant or unable to cope with stomaetc

11. Age at diagnosisMedian age in BC2001 and BCONMedian age in Skinner seriesMedian age in BA06 & SWOG 8710

12. Can we select good responders?Biological markersSelect patients for radiotherapy on basis of initial response to therapyRationale for Boston approach

13. Boston approach – Trimodality therapy

14. Results – Boston approach190 patients124 (65%) retained bladder41 (22%) Immediate cystectomy25 (13%) delayed cystectomyKaufman et al. Proc ASCO 2001 Abstract 683

15. Can we improve local control rates?Neoadjuvant therapySynchronous therapyAdjuvant therapy

16. MRC Trial - Metastasis Free SurvivalLancet. 1999

17. MRC Trial - Loco-regional controlLancet. 1999

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

19. Cisplatinum and RT +/- surgeryCoppin et al, J. Clin Onc. 14:2901-2907Coppin et al, J. Clin Onc. 14:2901-2907Cisplatinum and RT +/- surgery

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

21. RT+ CONRT aloneBCON – urinary and bowel toxicity > grade 2

22. Carbogen + NicotinamideHR 0.86 (0.74-1.0) p=0.06 at 3 yearsControl armBCON Primary endpoint – Local control

23. Carbogen + NicotinamideControl armBCON Overall survivalHR 0.85 (0.73-0.99) p=0.04 at 3 years

24. CTNoCTsRTRHDV RT BC2001: Trial designPatients with muscle invasive bladder cancerRANDOMISEReduced highdose volume RT+ synchronous chemotherapyStandard volume RT† + synchronous chemotherapyReduced highdose 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 regimenMMC 12mg/m25FU 500mg/m2/dRT 55 Gy/20 f or 64 Gy/32 fWeeks0 1 2 3 4 5 6 7 Target volume tumour + bladder + 1.5-2cmChemotherapy via peripherally inserted central line as outpatient therapy

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

27. Patient demographicsPerformance statusAge at randomisationMean (SD) 70.5 (8.2) yearsMedian (IQR) 71.9 (64.1 - 76.2) yearsOlder 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 toxicityProportions 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=0.19Worst grade of on-treatment toxicity by week

29. CTNo CTP-value*RTOGN=121N=107Overall10 (8.3%)17 (15.9%)0.07GI symptoms1 (0.8%)5 (4.7%)0.07GU symptoms9 (7.4%)12 (11.2%)0.30LENT/SOMN=117N=99Overall61 (52.1%)49 (49.5%)0.77Excl. sexual dysfunction33 (28.2%)27 (27.3%)0.78Late toxicityProportion of patients with a grade 3/4 toxicity at any time during follow-up (6 months onwards), up to 3 months before a recurrence:*Stratified Chi-square testPatients with no available assessment are excluded from tableLoco-regional disease free survival in chemotherapy randomisation 2-yr LRDFS 67% (95% CI: 58%, 74%)CT=53/18254% (95% CI: 46%, 62%)No CT=74/178HR = 0.67 (95% CI: 0.47, 0.95); p=0.03

30. Invasive loco-regional disease free survival in chemotherapy comparison 2-yr ILRDFS CT=28/18282% (95% CI: 75%, 88%)68% (95% CI: 59%, 75%)No CT=51/178HR = 0.53 (95% CI: 0.33, 0.84); p=0.007

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

32. OS in chemotherapy randomisation 2-yr OS 62% (95% CI: 54%, 68%)CT = 85/18260% (95% CI: 52%, 67%)No CT = 98/178HR = 0.82 (95% CI: 0.61, 1.10); p=0.16

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