Bladder Preservation for muscle invasive disease. Nicholas

Bladder Preservation for muscle invasive disease Nicholas James @Prof_Nick_James 1

Overview Evidence base for bladder preservation as alternative to surgery Chemoradiotherapy compared to radiotherapy alone

Age-standardised 5-year survival for bladder cancer 1999 2007 N Europe Ireland and UK Central Europe Southern Europe Eastern Europe Europe Rafael Marcos-Gragera, et al Urinary tract cancer survival in Europe 1999 2007: Results of the population-based study EUROCARE-5 European Journal of Cancer, Volume 51, Issue 15, 2015, 2217 2230 http://dx.doi.org/10.1016/j.ejca.2015.07.028

Background Bladder cancer outcomes have not significantly improved for 30 years Zehnder P, Studer UE, Skinner EC, Thalmann GN, Miranda G, Roth B, Cai J, Birkhauser FD, Mitra AP, Burkhard FC, Dorin RP, Daneshmand S, Skinner DG, Gill IS. Unaltered oncological outcomes of radical cystectomy with extended lymphadenectomy over three decades. BJU Int 2013;112:E51-8 Presented by: Nick James

IS SURVIVAL BETTER AFTER SURGERY?

Survival from UK Registry data 453 UK pts, 1993-1996 Ratio RT:cystectomy 3:1 10 year survival RT 22% Surgery 24% Munro NP, Sundaram SK, Weston PM, et al. A 10-year retrospective review of a nonrandomized cohort of 458 patients undergoing radical radiotherapy or cystectomy in Yorkshire, UK. Int J Radiat Oncol Biol Phys 2010;77:119-24.

Canadian Registry Data Bladder Cancer Variations in the use of total cystectomy and in the use of pelvic RT among the regions of Ontario were not associated with variations in survival. Survival was correlated with tumour related parameters Hayter CR, Paszat LF, Groome PA, et al: The management and outcome of bladder carcinoma in Ontario, 1982-1994. Cancer 89: 142-151, 2000

WHAT CAN WE LEARN FROM OTHER CANCERS?

Anal cancer Primary therapy was surgery up until mid- 1980s Various chemo-rt regimens showed high activity with range of agents including 5FU, MMC, cisplatinum during 1970s surgery as the primary therapeutic modality has been abandoned. Anal cancer: ESMO-ESSO-ESTRO Clinical Practice Guidelines for diagnosis, treatment and follow-up Ann Oncol (2014) 25 (suppl 3):iii10- iii20.doi: 10.1093/annonc/mdu159

CAN WE SALVAGE LOCAL FAILURES?

Primary vs Salvage Cystectomy Addla et al. The Journal of Urology Vol. 181, Issue 4, Supplement, Page 633

Are complication rates higher with salvage cystectomy? 426 primary and 420 salvage cystectomies Single institution 1970-2005 Differential Complication Rates Following Radical Cystectomy in the Irradiated and Nonirradiated Pelvis Vijay A.C. Ramani, Satish B. Maddineni, Ben R. Grey, Noel W. Clarke. Eur Urol 57 (2010) 1058 1063

Are complication rates higher with salvage cystectomy? Differential Complication Rates Following Radical Cystectomy in the Irradiated and Nonirradiated Pelvis Vijay A.C. Ramani, Satish B. Maddineni, Ben R. Grey, Noel W. Clarke. Eur Urol 57 (2010) 1058 1063

Are complication rates higher with salvage cystectomy? This large series from a high-volume centre demonstrates no difference in perioperative mortality in primary or postradiation salvage radical cystectomy. Similarly, there was no significant difference in the incidence of most of the surgical or medical complications.. Differential Complication Rates Following Radical Cystectomy in the Irradiated and Nonirradiated Pelvis Vijay A.C. Ramani, Satish B. Maddineni, Ben R. Grey, Noel W. Clarke. Eur Urol 57 (2010) 1058 1063

Age at diagnosis 1600 1400 Median age in BC2001 and BCON 1200 1000 Median age in USC series 800 600 Median age in BA06 & SWOG 8710 Male cases Female cases 400 200 0 0-4 5-9 10-14 15-19 20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79 80-84 85+

Choice of treatment Surgery and radiotherapy data relate to different segments of the population Hence age/fitness is important factor in treatment decisions

CHEMORADIATION VS RADIOTHERAPY ALONE

Synchronous Chemoradiotherapy 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)

Cisplatinum and RT +/- surgery Coppin CM, Gospodarowicz MK, James K, et al. Improved local control of invasive bladder cancer by concurrent cisplatin and preoperative or definitive radiation. Journal of Clinical Oncology 1996;14:2901-7

100 BCON Results Carbogen + Nicotinamide Relapse-free survival (%) 80 60 40 20 0 HR 0.86 (0.74-1.0) p=0.06 at 3 years LogŠrank p = 0.06 RT + CON 164 128 109 82 62 31 RT alone 161 111 84 62 50 21 0 12 24 36 48 60 Time from randomization (months) Control arm HR 0.85 (0.73-0.99) p=0.04 Relapse free survival Overall survival Hoskin PJ, Rojas AM, Bentzen SM, et al: Radiotherapy with concurrent carbogen and nicotinamide in bladder carcinoma. J Clin Oncol 28:4912-8, 2010

BC2001: Trial design Patients with muscle invasive bladder cancer RANDOMISE CT No CT Standard volume RT + synchronous chemotherapy Standard volume RT Reduced high dose volume RT + synchronous chemotherapy Reduced high dose volume RT srt RHDV RT Pragmatic design: Centres could offer double or either single randomisation

RTOG 6 month toxicity outcomes 80 70 60 50 40 Chemo RT RT only 30 20 10 0 Grade 0 Grade 1 Grade 2 Grade 3 Grade 4 Unknown n= 291, 145 RT only, 146 chemo-radiotherapy

Loco-regional disease free survival in chemotherapy randomisation Proportion locoregional disease-free 0.00 0.25 0.50 0.75 1.00 HR (95% CI) = 0.68 (0.48-0.96) Stratified logrank p= 0.03 0 12 24 36 48 60 72 Months since randomization N at risk (events) Chemo-RT 182 (35) 108 (14) 76 (3) 66 (1) 56 (1) 46 (1) 25 RT 178 (54) 96 (16) 69 (4) 58 (1) 44 (0) 35 (1) 18 Loco-regional control (invasive and non-invasive) Proportion invasive locoregional disease-free 0.00 0.25 0.50 0.75 1.00 HR (95% CI) = 0.57 (0.37-0.90) Stratified logrank p= 0.01 0 12 24 36 48 60 72 Months since randomization N at risk (events) Chemo-RT 182 (20) 121 (7) 93 (3) 79 (0) 66 (0) 54 (1) 32 RT 178 (37) 109 (11) 85 (2) 74 (2) 52 (0) 39 (0) 20 Invasive loco-regional control James et al, Radiotherapy with or without chemotherapy for invasive bladder cancer. NEJM 2012 366, 1477-1488

Patterns of recurrence after chemort Any recurrence 93/182 pts Loco-regional recurrence 53 Distant recurrence or second primary 40 Non-muscle invasive 25 Muscle invasive 18 Pelvic nodes 6 Metastasis 29 Second primary 11

10 YEAR OUTCOMES BC2001

Updated results - CT comparison 28 0.00 0.25 0.50 0.75 1.00 Loco-Regional Control (LRC) Invasive Loco-Regional Control HR (95% CI) = 0.61 (0.43-0.86) Stratified logrank p=0.004 Adjusted HR (95%CI): 0.59 (0.41 0.83), p=0.003 CT No CT 0 24 48 72 96 120 Months since randomisation N at risk (events) CT 182 (48) 77 (4) 65 (2) 54 (0) 28 (1) 8 (0) No CT 178 (71) 72 (5) 53 (5) 38 (2) 28 (1) 13 (0) 0.00 0.25 0.50 0.75 1.00 Invasive Loco-Regional Control (ILRC) HR (95% CI) = 0.55 (0.36-0.84) Stratified logrank p=0.006 Adjusted HR (95%CI): 0.52 (0.33 0.81), p=0.004 CT No CT 0 24 48 72 96 120 Months since randomisation N at risk (events) CT 182 (27) 94 (3) 77 (1) 66 (1) 37 (1) 13 (0) No CT 178 (50) 88 (4) 63 (1) 51 (2) 37 (1) 15 (0) Snapshot of data: July 2016, N=360, Median FUP 117.1 m

Study ID Study Study Study LRDFS - consistency across subgroups ID rtrand1 rtrand1 rtrand1 rtrand1 rtrand2 rtrand2 rtrand2 rtrand2 rtrand3 rtrand3 rtrand3 rtrand3 ptds1 ptds2 ID ID Randomised srt 63 0.57 Randomised RHDV 58 Elect srt 239 ptds1 ptds1 ptds1 RT dose 55Gy/20F 142 0.63 ptds2 ptds2 ptds2 RT dose 64Gy/32F 217 neoadj1 neoadj1 neoadj1 neoadj1 Neoadjuvant CT 118 0.59 No neoadjuvant CT 242 neoadj2 neoadj2 neoadj2 neoadj2 Primary Primary Primary Primary Primary analysis 360 HR (95% HR CI) (95% HR (95% CI) HR (95% CI) CI) N P-value Hazard ratio (95% CI) 0.79 (0.36, 0.79 1.77) 0.79 (0.36, (0.36, 0.79 1.77) (0.36, 1.77) 1.77 1.01 (0.37, 1.01 2.77) 1.01 (0.37, (0.37, 1.01 2.77) (0.37, 2.77) 2.77 0.59 (0.38, 0.59 0.91) 0.59 (0.38, (0.38, 0.59 0.91) (0.38, 0.91) 0.91 0.75 (0.41, 0.75 1.37) 0.75 (0.41, (0.41, 0.75 1.37) (0.41, 1.37) 1.37 0.63 (0.40, 0.63 0.97) 0.63 (0.40, (0.40, 0.63 0.97) (0.40, 0.97) 0.97 0.58 (0.32, 0.58 1.08) 0.58 (0.32, (0.32, 0.58 1.08) (0.32, 1.08) 1.08 0.72 (0.47, 0.72 1.12) 0.72 (0.47, (0.47, 0.72 1.12) (0.47, 1.12) 1.12 0.67 (0.47, 0.67 0.95) 0.67 (0.47, (0.47, 0.67 0.95) (0.47, 0.95) 0.95.2.2.5.2.5 1.2.5 2 1.5 1 2 1 2 2 Favours Favours CT Favours CT Favours CT Favours no CT CT Favours no Favours CT no CT no CT

Updated results - CT comparison 30 0.00 0.25 0.50 0.75 1.00 Overall Survival Bladder Cancer Specific survival HR (95% CI) = 0.88 (0.69-1.13) Stratified logrank p= 0.31 Adjusted HR (95%CI): 0.81 (0.62 1.04), p=0.100 CT No CT 0 24 48 72 96 120 Months since randomisation N at risk (events) CT 182 (69) 111 (20) 88 (5) 80 (12) 59 (11) 25 (6) No CT 178 (69) 107 (33) 73 (14) 58 (5) 47 (5) 18 (1) 0.00 0.25 0.50 0.75 1.00 Bladder Cancer specific Survival HR (95% CI) = 0.79 (0.59-1.06) Stratified logrank p= 0.11 Adjusted HR (95%CI): 0.73 (0.54 0.99), p=0.043 CT No CT 0 24 48 72 96 120 Months since randomisation N at risk (events) CT 182 (55) 111 (15) 88 (3) 80 (4) 59 (2) 25 (3) No CT 178 (60) 107 (25) 73 (9) 58 (3) 47 (0) 18 (1) Snapshot of data: July 2016, N=360, Median FUP 117.1 m

Updated results - CT comparison 31 0.00 0.25 0.50 0.75 1.00 Metastasis Free Survival Cystectomy Incidence HR (95% CI) = 0.78 (0.58-1.05) Stratified logrank p= 0.09 Adjusted HR (95%CI): 0.74 (0.54 1.00), p=0.051 CT No CT 0 24 48 72 96 120 Months since randomisation N at risk (events) CT 182 (61) 101 (10) 82 (2) 71 (3) 42 (2) 15 (2) No CT 178 (71) 95 (18) 67 (6) 53 (2) 39 (0) 17 (1) 0.00 0.25 0.50 0.75 1.00 Salvage Cystectomy Rate HR (95% CI) = 0.54 (0.31-0.95) Stratified logrank p= 0.03 2-year rate: CT 11% (7-17) No CT 17% (12-24) CT No CT 0 24 48 72 96 120 Months since randomisation N at risk (events) CT 182 (15) 98 (3) 79 (1) 71 (1) 51 (0) 20 (0) No CT 178 (25) 95 (3) 64 (4) 49 (1) 41 (0) 18 (0) Snapshot of data: July 2016, N=360, Median FUP 117.1 m

0.2.4.6.8 1 Proportion of invasive loco-regional control 0.2.4.6.8 1 Proportion of invasive loco-regional control Effect of Multivariate factors on ILRC No neoadjuvant CT 3-yr ILRC: Neoadjuvant CT 90.1% RT+CT 83.0% 82.9% No Res mass RT+CT RT No Res 71.4% 72.5% mass RT RT+CT Neoadjuvant chemotherapy and synchronous Residual 56.2% 56.0% mass RT+CT RT 35.3% Residual mass RT 3-yr ILRC: chemotherapy do different things 0 12 24 36 48 60 72 Months since randomisation 0 12 24 36 48 60 72 Months since randomisation 32

0.2.4.6.8 1 Overall Survival 0.2.4.6.8 1 Overall Survival 0.2.4.6.8 1 Overall Survival 0.2.4.6.8 1 Overall Survival Overall Survival WHO 0, Age 70 WHO 1-2, Age 70 0 12 24 36 48 60 72 Months since randomisation 0 12 24 36 48 60 72 Months since randomisation WHO 0, Age 80 WHO 1-2, Age 80 0 12 24 36 48 60 72 Months since randomisation RT, No Res Mass RT+CT, No Res Mass 0 12 24 36 48 60 72 Months since randomisation RT, Res Mass 33 RT+CT, Res Mass

Presence of residual mass, extent of resection and tumour size are related 0.00 0.25 0.50 0.75 1.00 Stage Logrank test p= 0.11 T2 T3-4 0.00 0.25 0.50 0.75 1.00 0 12 24 36 48 60 72 Months Size of tumour Logrank test p=0.001 <30mm >=30mm Unknown 0.00 0.25 0.50 0.75 1.00 0 12 24 36 48 60 72 Months Extent of tumour resection Logrank test p= 0.04 Biopsy/Not resected Complete resection Incomplete resection 0.00 0.25 0.50 0.75 1.00 0 12 24 36 48 60 72 Months Residual mass post resection Logrank test p=0.005 No Yes 0 12 24 36 48 60 72 Months The presence of residual mass was highly correlated with extent of resection 96% complete resections without residual mass 66% incomplete resections with residual mass

TURBT and residual mass Residual mass = high stage High stage = poor prognosis Therefore does not follow that RT only for patients with no mass post TURBT as these patients will do badly with surgery Also does not follow that TURBT actually needed

Should we change the diagnostic pathway?

What if breast cancer specialists behaved like urologists? Breast cancer would be diagnosed by 6 random needle cores in each breast Initial treatment would use a hot wire to scrape the middle of the tumour out, leaving the invasive bits round the edge to grow for several weeks while staging proceeds

What is the point of TURBT? Diagnosis Staging Treatment Palliation of symptoms from bladder

Non-muscle invasive bladder cancer 80% of total TURBT Diagnosis Staging Treatment Palliation of symptoms from bladder

Invasive bladder cancer TURBT Diagnosis Staging Treatment Palliation of symptoms from bladder - incomplete No - delayed Possibly If we could diagnose and stage a different way, treatment would be faster

TURBT in MIBC 5% overt bladder perforation rate 50% occult bladder perforation Large increase in circulating tumour cells Around 20% of pts have T2-4NxM0 disease but half of these get metastasis Could TURBT be actually spreading the cancer?

MRI Superficial vs invasive Sensitivity T2 88% T2 + DWI 88% T2 + DCE 94% All 3 94% Specificity T2 74% T2 + DWI 100% T2 + DCE 86% All 3 100% TURBT pathological upstaging at cystectomy 40% Takeuchi M, Sasaki S, Ito M, Okada S, Takahashi S, Kawai T, Suzuki K, Oshima H, Hara M, Shibamoto Y. Urinary bladder cancer: diffusion-weighted MR imaging--accuracy for diagnosing T stage and estimating histologic grade. Radiology 2009;251:112-21

Ideal new pathway NMIBC Identify on imaging and biopsy/cytology Fast track to TURBT and subsequent therapy MIBC Stage with biopsy and MRI Fast track to definitive therapy TURBT only if urgently needed for symptoms e.g. intractable bleeding Problem: need to separate NMIBC from MIBC

BladderPath Trial Newly presented haematuria patients Randomise Standard care pathway Marker directed pathway Outcome measures: Stage 1: Feasibility, safety Stage 2: Time to primary treatment Stage 3: Failure free survival

BladderPath: Image Directed Redesign of Bladder Cancer Treatment Pathways Newly presented haematuria patients PIS given with Haematuria Clinic appointment letter Haematuria Clinic Informed consent 1 Flexible cystoscopy + cytology + imaging+ biopsy Diagnosis given Informed consent 2 Informed consent 1: Consenting all patients to biopsy (not standard) and collection of urine sample Patients without diagnosis of bladder cancer are excluded from study Informed consent 2: Consenting bladder cancer patients to the trial Randomisation A Probable NMIBC Pathway 1 (standard) TURBT Possible MIBC B C Probable NMIBC TURBT Pathway 2 Possible MIBC MRI D Feasibility test: H/D > 80% Intermediate test: Time from first consent to DT-F vs Time from first consent to DT-H E NMIBC MIBC F G NMIBC MIBC H Adjuvant treatment Chem o RT Surgery 1 st Definitive Treatment for F (DT-F) TURBT Chem RT Surgery 1 st o Definitive Treatment for H (DT-H)

BladderPath Feasibility stage 150 patients Intermediate stage event driven, at least 20 MIBC patients (approximately 80-100 patients will need to be recruited overall). Final clinical stage event driven, (approximately 950 patients)

Patient 1 Presented with haematuria Large mass on flexible cystoscopy Biopsy G3TCC Proceeded direct to chemotherapy

Patient 2 Haematuria Flexible cystoscopy: 1.5 cm papillary tumour on left lateral wall Histology G2 TCC Stage T1N0M0

Patient 3 Transplant pt Solid mass at dome of bladder, partial TURBT done T4 on MRI with bowel infiltration Lower bowel defunctioned

Patient 3 (cont) Completed 55Gy/20 fractions + 5FU/MMC Post RT cystoscopy pathological CR

BladderPath feasibility early impressions MRI protocol works well to distinguish T1 from T2 and above Team happy to make treatment decisions without full TURBT Post therapy MRI can be used for treatment assessment The trial is ongoing

But radiotherapy leaves you a small poorly functioning bladder

Mean change from baseline Mean change from baseline Mean change from baseline Mean change from baseline -4-2 0 2 4-8 -6-4 -2 0 2 4 6 8 B/L EOT 6m No. with data: N 327 278-4 -2 0 2 4-8 -6-4 -2 0 2 4 6 8 BLCS Change BLCS from in Change Baseline FACT BLCS from Score Change Baseline from Score domains Baseline Score BLCS (all Change patients) from Baseline Score Mean change from baseline Physical Well-Being Change from Baseline Score B/L EOT 6m No. with data: N 325 275 * Mean change from baseline -8-6 -4-2 0 2 4 6 8 12m B/L EOT 6m2 years12m B/L EOT3 6m years 2 years 12m 4 years 3 years 2 years 5 years 4 years 3 years No. with data: No. with data: 227 N 325 275 166 227 N 325 275 143 166 227 122 143 166 106 122 143 12m 230 Mean change from baseline Mean 95% MeanCI Mean 95% CI 2 years 165-8 -6-4 -2 0 2 4 6 8 Mean 3 years 4 years 5 years 144 122 104 95% CI Emotional Well-Being Change from Baseline Score * * * B/L EOT 6m No. with data: N 325 275-8 -6-4 -2 0 2 4 6 8 * * * * Mean change from baseline Mean change from baseline Mean change from baseline Mean change from baseline 95% CI -4-2 0 2 4-8 -6-4 -2 0 2 4 6 8 BLCS Change BLCS from Change Baseline BLCS from Score Change Baseline from Score Baseline Score Mean change from baseline -8-6 -4-2 0 2 4 6 8 12m B/L EOT 6m2 years12m B/L EOT3 6m years 2 years 12m 4 years 3 years 2 years 5 years 4 years 3 years No. with data: No. with data: 227 N 325 275 166 227 N 325 275 143 166 227 122 143 166 106 122 143 Mean 95% MeanCI Mean 95% CI 95% CI Mean change from baseline 5 years 4 years B/L EOT 6m 5 years 12m B/L EOT 6m2 years12m B/L EOT3 6m years 2 years 12m No. with data: No. with data: No. with data: 106 122N 325 275 106227 N 325 275 166 227 N 325 275 143 166 227 B/L EOT 6m No. with data: N 317 273-4 -2 0 2 4-8 -6-4 -2 0 2 4 6 8-8 -6-4 -2 0 2 4 6 8 Social Well-Being Change from Baseline Score Mean change from baseline 12m 225 Mean change from baseline 2 years 162 Mean BLCS Change BLCS from Change Baseline from Score Base -8-6 -4-2 0 2 4 6 8 3 years 4 years 3 years 2 years 5 years 4 years 3 years 122 143 166 106 122 143 Mean 95% MeanCI Mean 95% CI 9 4 years 5 years 140 117 101 95% CI Functional Well-Being Change from Baseline Score 5 years 4 years B/L EOT 6m 5 years 12m B/L EOT 6m2 years12m B/L EOT3 6m years 2 years 12m No. with data: No. with data: No. with data: 106 122N 325 275 106227 N 325 275 166 227 N 325 275 143 166 227 * BLCS Change BLCS from Change Baseline BLCS from Score Change Baseline from Score Base -8-6 -4-2 0 2 4 6 8 Mean change from baseline -8-6 -4-2 0 2 4 6 8 4 years 3 years 2 years 5 years 4 years 3 years 122 143 166 106 122 143 Mean 95% MeanCI Mean 95% CI 9 B/L EOT 6m No. with data: N 326 276 12m 229 2 years 167 Mean 3 years 142 95% CI 4 years 120 5 years 104 B/L EOT 6m No. with data: N 324 277 *Paired t-test, p 0.01 12m 228 2 years 165 Mean 3 years 142 95% CI 4 years 120 5 years 105

CAN WE SELECT PATIENTS FOR BLADDER PRESERVATION?

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

Patients unsuitable for (chemo)rt Poor bladder function Highly symptomatic bladders Extensive CIS Prior pelvic RT Inflammatory bowel disease Certain genetic disorders

Conclusions No convincing evidence surgery superior to primary bladder preservation with salvage surgery Synchronous chemo-radiation is safe and improves pelvic control and is complementary to neoadjuvant treatment Patient reported outcomes and long term follow up confirm the benefits reported in BC2001